Substituted pyrimidine Bmi-1 inhibitors

ABSTRACT

Amine substituted pyrimidine compounds and forms thereof that inhibit the function and reduce the level of B-cell specific Moloney murine leukemia virus integration site 1 (Bmi-1) protein and methods for their use to inhibit Bmi-1 function and reduce the level of Bmi-1 to treat a cancer mediated by Bmi-1 are described herein.

INTRODUCTION

Substituted pyrimidine compounds that inhibit the function of the B-cellspecific Moloney murine leukemia virus integration site 1 (Bmi-1)protein and reduce the level thereof and methods of using such compoundsto treat a cancer mediated by Bmi-1 are described. More particularly,amine substituted pyrimidine compounds that inhibit Bmi-1 function andreduce the level of Bmi-1 are useful for treating a cancer mediated byBmi-1.

BACKGROUND

Bmi-1 was originally identified by its over-expression in variousleukemias and lymphomas. Subsequently, Bmi-1 has been shown to haveoncogenic activity when overexpressed in normal cells and to play a rolein the maintenance of cancer stem cell populations. Bmi-1 is elevated inmany tumor types and is important in hematologic cancers and many solidtumors, including brain cancers. Reduction of Bmi-1 levels in tumorcells by siRNA causes apoptosis and/or cell senescence and increasessusceptibility to cytotoxic agents. Bmi-1 serves as the key regulatorycomponent of the PRC1 complex (polycomb repressive complex-1), but hasno enzymatic activity. Therefore, targeting Bmi-1 by traditional drugdiscovery methods has been problematic.

Since Bmi-1 levels within cells are tightly regulated through bothtranscriptional and post-transcriptional mechanisms, this regulation canbe exploited to target this important protein. Accordingly, thereremains a need to provide compounds that inhibit Bmi-1 function andreduce the level of Bmi-1 to treat a cancer mediated by Bmi-1.

SUMMARY

Certain amine substituted pyrimidine compounds that inhibit Bmi-1function and reduce the level of Bmi-1 and methods for their use totreat a cancer mediated by Bmi-1 are described herein.

A compound of Formula (I) is described:

wherein X, R₁, R₂, R₃ and R₄ are as defined herein, including forms andpharmaceutical compositions thereof, and methods of using suchcompounds, forms or compositions thereof to treat a cancer mediated byBmi-1 in a human subject in need thereof.

DETAILED DESCRIPTION

Amine substituted pyrimidine compounds for use in inhibiting Bmi-1function and reducing the level of Bmi-1 and in methods for treating acancer mediated by Bmi-1 thereby are described.

In one embodiment is a compound of Formula (I):

or a form thereof, wherein

-   X is N or N substituted with an oxygen atom substituent to form an    N-oxide;-   R₁ is heteroaryl or heterocyclyl optionally substituted on a carbon    atom ring member with one, two, three or four R₅ substituents or on    a nitrogen atom ring member with an oxygen atom substituent to form    an N-oxide;-   R₂ is hydrogen, cyano, halo, hydroxyl, nitro, C₁₋₈alkyl,    hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    (C₁₋₈alkyl)₂-amino, hydroxyl-amino, hydroxyl-C₁₋₈alkyl-amino,    C₁₋₈alkoxy-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio, C₁₋₈alkyl-carbonyl,    C₁₋₈alkyl-carbonyl-amino, amino-carbonyl, C₁₋₈alkyl-amino-carbonyl,    (C₁₋₈alkyl)₂-amino-carbonyl, amino-carbonyl-amino,    C₁₋₈alkyl-amino-carbonyl-amino, (C₁₋₈alkyl)₂-amino-carbonyl-amino,    C₁₋₈alkoxy-carbonyl, C₁₋₈alkoxy-carbonyl-amino, amino-sulfonyl,    C₁₋₈alkyl-amino-sulfonyl, (C₁₋₈alkyl)₂-amino-sulfonyl,    amino-sulfonyl-amino, C₁₋₈alkyl-amino-sulfonyl-amino,    (C₁₋₈alkyl)₂-amino-sulfonyl-amino, P(O)(R₇)₂-amino or heteroaryl,    wherein heteroaryl is optionally substituted with one, two, three or    four C₁₋₈alkyl substituents;-   R₃ is hydrogen, cyano, halo or C₁₋₈alkyl, amino, C₁₋₈alkyl-amino or    (C₁₋₈alkyl)₂-amino;-   R₄ is C₃₋₁₄cycloalkyl, aryl, heteroaryl or heterocyclyl, each    optionally substituted with one, two, three or four R₆ substituents;-   R₅ is independently selected from cyano, halo, hydroxyl, nitro, oxo,    C₁₋₈alkyl, cyano-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl,    C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, halo-C₁₋₈alkoxy, C₂₋₈alkenyl,    C₁₋₈alkoxy-C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy-C₂₋₈alkynyl,    carboxyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl-amino,    hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,    hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio,    C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-amino,    C₁₋₈alkyl-carbonyl-oxy, C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl,    C₁₋₈alkoxy-carbonyl, C₁₋₈alkoxy-carbonyl-C₁₋₈alkyl,    C₁₋₈alkoxy-carbonyl-amino, C₁₋₈alkyl-sulfonyl, C₃₋₁₄cycloalkyl,    aryl, aryl-C₁₋₈alkyl, aryl-amino, aryl-C₁₋₈alky-amino, heteroaryl,    heteroaryl-C₁₋₈alkyl or heterocyclyl, wherein C₃₋₁₄cycloalkyl, aryl,    heteroaryl or heterocyclyl and the aryl and heteroaryl portions of    aryl-C₁₋₈alkyl, aryl-amino, aryl-C₁₋₈alky-amino and    heteroaryl-C₁₋₈alkyl are each optionally substituted with one, two,    three or four halo, C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl,    C₁₋₈alkoxy, halo-C₁₋₈alkoxy, hydroxyl-C₁₋₈alkoxy or carboxyl    substituents;-   R₆ is independently selected from cyano, halo, hydroxyl, nitro,    C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,    halo-C₁₋₈alkoxy, C₂₋₈alkenyl, C₁₋₈alkoxy-C₂₋₈alkenyl, C₂₋₈alkynyl,    C₁₋₈alkoxy-C₂₋₈alkynyl, carboxyl, formyl, formyl-oxy,    C₁₋₈alkyl-carbonyl, halo-C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-thio,    halo-C₁₋₈alkyl-thio, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,    C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-oxy,    C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,    halo-C₁₋₈alkoxy-carbonyl, C₁₋₈alkoxy-carbonyl-C₁₋₈alkyl,    C₁₋₈alkoxy-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino-C₁₋₈alkyl,    amino-carbonyl, C₁₋₈alkyl-amino-carbonyl,    (C₁₋₈alkyl)₂-amino-carbonyl, C₁₋₈alkyl-carbonyl-amino,    C₁₋₈alkyl-carbonyl-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,    amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,    (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino, hydroxyl-C₁₋₈alkyl-amino,    hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,    hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, imino-C₁₋₈alkyl,    hydroxyl-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyl, halo-C₁₋₈alkyl-sulfonyl, amino-sulfonyl,    C₁₋₈alkyl-amino-sulfonyl, (C₁₋₈alkyl)₂-amino-sulfonyl, B(OR₈)₂,    C₃₋₁₄cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein    C₃₋₁₄cycloalkyl, heterocyclyl, aryl and heteroaryl are each    optionally substituted with one, two, three or four halo or    C₁₋₈alkyl substituents;-   R₇ is independently hydroxyl or (C₁₋₈alkoxy)_(n), wherein n    represents an integer from 1 to 5; and,-   R₈ is independently hydrogen or C₁₋₈alkyl, wherein C₁₋₈alkyl    optionally forms a heterocyclyl ring system with the oxygen atoms of    attachment.

Another embodiment includes a compound of Formula (I), wherein X is N.

Another embodiment includes a compound of Formula (I), wherein X is Nsubstituted with an oxygen atom substituent to form an N-oxide.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl or heterocyclyl selected from1H-pyrazolyl, 1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl,2H-indazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 1H-benzimidazolyl,imidazo[2,1-b][1,3]thiazolyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-c]pyrimidinyl, imidazo[1,2-a]pyridinyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl,1H-imidazo[4,5-c]pyridinyl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyrazinyl,imidazo[1,2-a]pyrimidinyl, 7H-purinyl or quinolinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl or heterocyclyl selected from1H-pyrazolyl, 1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl,2H-indazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 1H-benzimidazolyl,imidazo[2,1-b][1,3]thiazolyl, pyrazolo[1,5-a]pyridinyl,imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl,1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyrazinyl,imidazo[1,2-a]pyrimidinyl, 7H-purinyl or quinolinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl or heterocyclyl selected from1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-5-yl, 1,2-oxazol-4-yl,1,2-oxazol-5-yl, pyridin-4-yl, 1H-indol-1-yl, 1H-indol-3-yl,1H-indol-4-yl, 2H-indazol-3-yl, 4,5,6,7-tetrahydro-2H-indazol-3-yl,1H-benzimidazol-1-yl, imidazo[2,1-b][1,3]thiazol-5-yl,pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,pyrazolo[1,5-a]pyridin-7-yl, pyrazolo[1,5-c]pyrimidin-3-yl,imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-5-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl,1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl,imidazo[1,2-a]pyrazin-3-yl, imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-ylor quinolin-4-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl or heterocyclyl selected from1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-5-yl, 1,2-oxazol-4-yl,1,2-oxazol-5-yl, pyridin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl,2H-indazol-3-yl, 4,5,6,7-tetrahydro-2H-indazol-3-yl,1H-benzimidazol-1-yl, imidazo[2,1-b][1,3]thiazol-5-yl,pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-7-yl,imidazo[1,2-a]pyridin-3-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl,1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl,imidazo[1,2-a]pyrazin-3-yl, imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-ylor quinolin-4-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl or heterocyclyl selected from1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-5-yl, 1,2-oxazol-4-yl,1,2-oxazol-5-yl, pyridin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl,2H-indazol-3-yl, 4,5,6,7-tetrahydro-2H-indazol-3-yl,1H-benzimidazol-1-yl, imidazo[2,1-b][1,3]thiazol-5-yl,pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-7-yl,imidazo[1,2-a]pyridin-3-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl,1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl, 7H-purin-7-yl orquinolin-4-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazolyl,1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl, 2H-indazolyl,1H-benzimidazolyl, imidazo[2,1-b][1,3]thiazolyl,pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-c]pyrimidinyl,imidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl,1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyrazinyl,imidazo[1,2-a]pyrimidinyl, 7H-purinyl or quinolinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazolyl,1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl, 2H-indazolyl,1H-benzimidazolyl, imidazo[2,1-b][1,3]thiazolyl,pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl,imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 7H-purinyl orquinolinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazolyl,1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl, 2H-indazolyl,1H-benzimidazolyl, imidazo[2,1-b][1,3]thiazolyl,pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 7H-purinyl orquinolinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazolyl,1H-indolyl, 1H-benzimidazolyl, pyrazolo[1,5-a]pyridinyl,imidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl or imidazo[1,2-a]pyrimidinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazolyl,1,2-oxazolyl, 1H-benzimidazolyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-c]pyrimidinyl, imidazo[1,2-a]pyridinyl,1H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl or quinolinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazolyl,1H-indolyl, 1H-benzimidazolyl, pyrazolo[1,5-a]pyridinyl,imidazo[1,2-a]pyridinyl or 1H-imidazo[4,5-b]pyridinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from imidazo[1,2-a]pyrazinylor imidazo[1,2-a]pyrimidinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted imidazo[1,2-a]pyrazinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted imidazo[1,2-a]pyrimidinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazol-4-yl,1H-imidazol-1-yl, 1H-imidazol-5-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl,pyridin-4-yl, 1H-indol-1-yl, 1H-indol-3-yl, 1H-indol-4-yl,2H-indazol-3-yl, 1H-benzimidazol-1-yl, imidazo[2,1-b][1,3]thiazol-5-yl,pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,pyrazolo[1,5-a]pyridin-7-yl, pyrazolo[1,5-c]pyrimidin-3-yl,imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl,imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-1-yl,1H-imidazo[4,5-c]pyridin-1-yl, imidazo[1,2-a]pyrazin-3-yl,imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-yl or quinolin-4-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazol-4-yl,1H-imidazol-1-yl, 1H-imidazol-5-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl,pyridin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl, 2H-indazol-3-yl,1H-benzimidazol-1-yl, imidazo[2,1-b][1,3]thiazol-5-yl,pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-7-yl,1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,imidazo[1,2-a]pyrazin-3-yl, imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-ylor quinolin-4-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazol-4-yl,1H-imidazol-1-yl, 1H-imidazol-5-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl,pyridin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl, 2H-indazol-3-yl,1H-benzimidazol-1-yl, imidazo[2,1-b][1,3]thiazol-5-yl,pyrazolo[1,5-a]pyridin-7-yl, imidazo[1,2-a]pyridin-5-yl,1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,imidazo[1,2-a]pyrazin-3-yl, imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-ylor quinolin-4-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazol-4-yl,1H-indol-1-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-benzimidazol-1-yl,pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,pyrazolo[1,5-a]pyridin-7-yl, imidazo[1,2-a]pyridin-2-yl,imidzo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,1H-imidazo[4,5-b]pyridin-1-yl, imidazo[1,2-a]pyrazin-3-yl orimidazo[1,2-a]pyrimidin-3-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazol-4-yl,1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1H-benzimidazol-1-yl,pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,pyrazolo[1,5-a]pyridin-7-yl, pyrazolo[1,5-c]pyrimidin-3-yl,imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl,imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-1-yl,imidazo[1,2-a]pyrimidin-3-yl or quinolin-4-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heteroaryl selected from 1H-pyrazol-4-yl,1H-indol-3-yl, 1H-benzimidazol-1-yl, pyrazolo[1,5-a]pyridin-2-yl,pyrazolo[1,5-a]pyridin-3-yl, imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyridin-3-yl, 1H-imidazo[4,5-b]pyridin-1-yl,imidazo[1,2-a]pyrazin-3-yl or imidazo[1,2-a]pyrimidin-3-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted imidazo[1,2-a]pyrazin-3-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted imidazo[1,2-a]pyrimidin-3-yl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heterocyclyl selected from4,5,6,7-tetrahydro-2H-indazolyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl or4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl.

Another embodiment includes a compound of Formula (I), wherein R₁ isoptionally substituted heterocyclyl selected from4,5,6,7-tetrahydro-2H-indazol-3-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl or4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl.

Another embodiment includes a compound of Formula (I), wherein R₂ iscyano, halo, hydroxyl, nitro, C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, hydroxyl-amino,hydroxyl-C₁₋₈alkyl-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-amino, amino-carbonyl,C₁₋₈alkyl-amino-carbonyl, (C₁₋₈alkyl)₂-amino-carbonyl,amino-carbonyl-amino, C₁₋₈alkyl-amino-carbonyl-amino,(C₁₋₈alkyl)₂-amino-carbonyl-amino, C₁₋₈alkoxy-carbonyl,C₁₋₈alkoxy-carbonyl-amino, amino-sulfonyl, C₁₋₈alkyl-amino-sulfonyl,(C₁₋₈alkyl)₂-amino-sulfonyl, amino-sulfonyl-amino,C₁₋₈alkyl-amino-sulfonyl-amino, (C₁₋₈alkyl)₂-amino-sulfonyl-amino,P(O)(R₇)₂-amino or heteroaryl, wherein heteroaryl is optionallysubstituted with one, two, three or four C₁₋₈alkyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₂ iscyano, halo, nitro, C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, amino,hydroxyl-amino, hydroxyl-C₁₋₈alkyl-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,C₁₋₈alkyl-thio, amino-carbonyl, amino-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, amino-sulfonyl-amino or heteroaryl, whereinheteroaryl is optionally substituted with one, two, three or fourC₁₋₈alkyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₂ iscyano, halo, hydroxyl, nitro, C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, hydroxyl-amino,hydroxyl-C₁₋₈alkyl-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-amino, amino-carbonyl,C₁₋₈alkyl-amino-carbonyl, (C₁₋₈alkyl)₂-amino-carbonyl,amino-carbonyl-amino, C₁₋₈alkyl-amino-carbonyl-amino,(C₁₋₈alkyl)₂-amino-carbonyl-amino, C₁₋₈alkoxy-carbonyl,C₁₋₈alkoxy-carbonyl-amino, amino-sulfonyl, C₁₋₈alkyl-amino-sulfonyl,(C₁₋₈alkyl)₂-amino-sulfonyl, amino-sulfonyl-amino,C₁₋₈alkyl-amino-sulfonyl-amino, (C₁₋₈alkyl)₂-amino-sulfonyl-amino orP(O)(R₇)₂-amino.

Another embodiment includes a compound of Formula (I), wherein R₂ iscyano, halo, nitro, C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, amino,hydroxyl-amino, hydroxyl-C₁₋₈alkyl-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,C₁₋₈alkyl-thio, amino-carbonyl, amino-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino or amino-sulfonyl-amino.

Another embodiment includes a compound of Formula (I), wherein R₂ isheteroaryl, wherein heteroaryl is optionally substituted with one, two,three or four C₁₋₈alkyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₂heteroaryl is optionally substituted 1H-pyrrolyl.

Another embodiment includes a compound of Formula (I), wherein R₂heteroaryl is optionally substituted 1H-pyrrol-1-yl.

Another embodiment includes a compound of Formula (I), wherein R₃ ishydrogen.

Another embodiment includes a compound of Formula (I), wherein R₃ iscyano, halo, C₁₋₈alkyl, amino, C₁₋₈alkyl-amino or (C₁₋₈alkyl)₂-amino.

Another embodiment includes a compound of Formula (I), wherein R₃ iscyano, halo, C₁₋₈alkyl or amino.

Another embodiment includes a compound of Formula (I), wherein R₃ ishalo.

Another embodiment includes a compound of Formula (I), wherein R₃ isC₁₋₈alkyl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted C₃₋₁₄cycloalkyl selected from2,3-dihydro-1H-indenyl; or, optionally substituted aryl selected fromphenyl or naphthyl; or, optionally substituted heteroaryl selected from1,3-thiazolyl, 1,2-oxazolyl, pyridinyl, pyrimidinyl, 1H-indolyl,benzofuranyl, benzooxazolyl, 1,3-benzothiazolyl, quinolinyl orisoquinolinyl; or, optionally substituted heterocyclyl selected from1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted C₃₋₁₄cycloalkyl selected from2,3-dihydro-1H-indenyl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted C₃₋₁₄cycloalkyl selected from2,3-dihydro-1H-inden-2-yl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted aryl selected from phenyl or naphthyl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted heteroaryl selected from 1,3-thiazolyl,1,2-oxazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, benzofuranyl,benzooxazolyl, 1,3-benzothiazolyl, quinolinyl or isoquinolinyl; or,optionally substituted heterocyclyl selected from 1,3-benzodioxolyl or2,3-dihydro-1,4-benzodioxinyl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted heteroaryl selected from 1,3-thiazol-2-yl,1,2-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl,1H-indol-5-yl, benzofuran-5-yl, benzooxazol-5-yl, 1,3-benzothiazol-2-yl,quinolin-3-yl, quinolin-6-yl or isoquinolin-3-yl; or, optionallysubstituted heterocyclyl selected from 1,3-benzodioxol-5-yl or2,3-dihydro-1,4-benzodioxin-6-yl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted heteroaryl selected from 1,3-thiazolyl,1,2-oxazolyl, pyridinyl, pyridinyl, pyrimidinyl, 1H-indolyl,benzofuranyl, benzooxazolyl, 1,3-benzothiazolyl, quinolinyl orisoquinolinyl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted heteroaryl selected from 1,3-thiazol-2-yl,1,2-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl,1H-indol-5-yl, benzofuran-5-yl, benzooxazol-5-yl, 1,3-benzothiazol-2-yl,quinolin-3-yl, quinolin-6-yl or isoquinolin-3-yl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted heterocyclyl selected from 1,3-benzodioxolyl or2,3-dihydro-1,4-benzodioxinyl.

Another embodiment includes a compound of Formula (I), wherein R₄ isoptionally substituted heterocyclyl selected from 1,3-benzodioxol-5-ylor 2,3-dihydro-1,4-benzodioxin-6-yl.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from cyano, halo, hydroxyl, nitro, C₁₋₈alkyl,cyano-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl, halo-C₁₋₈alkoxy, C₂₋₈alkenyl,C₁₋₈alkoxy-C₂₋₈alkenyl, carboxyl, amino, C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl, C₁₋₈alkyl-sulfonyl, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl, aryl-amino, aryl-C₁₋₈alky-amino, heteroaryl orheteroaryl-C₁₋₈alkyl, wherein heteroaryl and the aryl and heteroarylportions of aryl-C₁₋₈alkyl, aryl-amino, aryl-C₁₋₈alky-amino andheteroaryl-C₁₋₈alkyl are each optionally substituted with one, two,three or four halo or halo-C₁₋₈alkoxy substituents.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from cyano, halo, hydroxyl, nitro, oxo,C₁₋₈alkyl, cyano-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl,C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, halo-C₁₋₈alkoxy, C₂₋₈alkenyl,C₁₋₈alkoxy-C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy-C₂₋₈alkynyl, carboxyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl-amino, hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkyl-carbonyl-oxy,C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,C₁₋₈alkoxy-carbonyl-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl-amino orC₁₋₈alkyl-sulfonyl.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from cyano, halo, hydroxyl, nitro, C₁₋₈alkyl,cyano-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl, halo-C₁₋₈alkoxy, C₂₋₈alkenyl,C₁₋₈alkoxy-C₂₋₈alkenyl, carboxyl, amino, C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl or C₁₋₈alkyl-sulfonyl.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from optionally substituted C₃₋₁₄cycloalkylselected from cyclopropyl or cyclobutyl; or, aryl, aryl-C₁₋₈alkyl,aryl-amino or aryl-C₁₋₈alky-amino optionally substituted on aryl and thearyl portions, wherein aryl is selected from phenyl; and, wherein theoptional substituents on C₃₋₁₄cycloalkyl, aryl and the aryl portions areselected from one, two, three or four halo, C₁₋₈alkyl, halo-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, hydroxyl-C₁₋₈alkyl orcarboxyl substituents; or, heteroaryl or heteroaryl-C₁₋₈alkyl optionallysubstituted on heteroaryl and the heteroaryl portion, wherein heteroarylis selected from tetrazolyl or pyridinyl; and, wherein the optionalsubstituents on heteroaryl and the heteroaryl portion are selected fromone, two, three or four halo, C₁₋₈alkyl, halo-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, hydroxyl-C₁₋₈alkyl orcarboxyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from optionally substituted C₃₋₁₄cycloalkylselected from cyclopropyl or cyclobutyl; or, aryl-C₁₋₈alkyl, aryl-aminoor aryl-C₁₋₈alky-amino optionally substituted on the aryl portions,wherein aryl is selected from phenyl; and, wherein the optionalsubstituents on C₃₋₁₄cycloalkyl and the aryl portions are selected fromone, two, three or four halo or halo-C₁₋₈alkoxy substituents; or,heteroaryl or heteroaryl-C₁₋₈alkyl optionally substituted on heteroaryland the heteroaryl portion, wherein heteroaryl is selected fromtetrazolyl or pyridinyl; and, wherein the optional substituents onheteroaryl and the heteroaryl portion are selected from one, two, threeor four halo or halo-C₁₋₈alkoxy substituents.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from optionally substituted C₃₋₁₄cycloalkylselected from cyclopropyl or cyclobutyl.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from aryl, aryl-C₁₋₈alkyl, aryl-amino oraryl-C₁₋₈alky-amino optionally substituted on aryl and the arylportions, wherein aryl is selected from phenyl; and, wherein theoptional substituents are selected from one, two, three or four halo,C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, hydroxyl-C₁₋₈alkyl or carboxyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from aryl-C₁₋₈alkyl, aryl-amino oraryl-C₁₋₈alky-amino optionally substituted on the aryl portions, whereinaryl is selected from phenyl; and, wherein the optional substituents areselected from one, two, three or four halo or halo-C₁₋₈alkoxysubstituents.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from heteroaryl or heteroaryl-C₁₋₈alkyloptionally substituted on heteroaryl and the heteroaryl portion, whereinheteroaryl is selected from tetrazolyl or pyridinyl; and, wherein theoptional substituents are selected from one, two, three or four halo,C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, hydroxyl-C₁₋₈alkyl or carboxyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from heteroaryl or heteroaryl-C₁₋₈alkyloptionally substituted on heteroaryl and the heteroaryl portion, whereinheteroaryl is selected from tetrazolyl or pyridinyl; and, wherein theoptional substituents are selected from one, two, three or four halo orhalo-C₁₋₈alkoxy substituents.

Another embodiment includes a compound of Formula (I), wherein R₅ isindependently selected from heteroaryl or heteroaryl-C₁₋₈alkyloptionally substituted on heteroaryl and the heteroaryl portion, whereinheteroaryl is selected from 2H-tetrazol-2-yl, tetrazol-1-yl,pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; and, wherein the optionalsubstituents are selected from one, two, three or four halo orhalo-C₁₋₈alkoxy substituents.

Another embodiment includes a compound of Formula (I), wherein R₆ isindependently selected from cyano, halo, hydroxyl, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,C₂₋₈alkenyl, C₂₋₈alkynyl, formyl, formyl-oxy, C₁₋₈alkyl-carbonyl,halo-C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-thio, halo-C₁₋₈alkyl-thio, amino,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy-carbonyl, amino-carbonyl,C₁₋₈alkyl-amino-carbonyl, amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino, hydroxyl-C₁₋₈alkyl-amino,hydroxyl-imino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl, B(OR₈)₂, C₃₋₁₄cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein C₃₋₁₄cycloalkyl, heterocyclyl,aryl and heteroaryl are each optionally substituted with one, two, threeor four halo or C₁₋₈alkyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₆ isindependently selected from cyano, halo, hydroxyl, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,C₂₋₈alkenyl, C₁₋₈alkoxy-C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy-C₂₋₈alkynyl, carboxyl, formyl, formyl-oxy,C₁₋₈alkyl-carbonyl, halo-C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-thio,halo-C₁₋₈alkyl-thio, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-oxy,C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,halo-C₁₋₈alkoxy-carbonyl, C₁₋₈alkoxy-carbonyl-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino-C₁₋₈alkyl,amino-carbonyl, C₁₋₈alkyl-amino-carbonyl, (C₁₋₈alkyl)₂-amino-carbonyl,C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkyl-carbonyl-amino-C₁₋₈alkyl,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,hydroxyl-C₁₋₈alkyl-amino, hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, imino-C₁₋₈alkyl,hydroxyl-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyl, halo-C₁₋₈alkyl-sulfonyl, amino-sulfonyl,C₁₋₈alkyl-amino-sulfonyl, (C₁₋₈alkyl)₂-amino-sulfonyl or B(OR₈)₂.

Another embodiment includes a compound of Formula (I), wherein R₆ isindependently selected from cyano, halo, hydroxyl, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,C₂₋₈alkenyl, C₂₋₈alkynyl, formyl, formyl-oxy, C₁₋₈alkyl-carbonyl,halo-C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-thio, halo-C₁₋₈alkyl-thio, amino,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy-carbonyl, amino-carbonyl,C₁₋₈alkyl-amino-carbonyl, amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino, hydroxyl-C₁₋₈alkyl-amino,hydroxyl-imino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl, C₁₋₈alkyl-amino-sulfonylor B(OR₈)₂.

Another embodiment includes a compound of Formula (I), wherein R₆ isindependently selected from C₃₋₁₄cycloalkyl, heterocyclyl, aryl orheteroaryl, wherein C₃₋₁₄cycloalkyl, heterocyclyl, aryl and heteroarylare each optionally substituted with one, two, three or four halo orC₁₋₈alkyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₆ isindependently selected from C₃₋₁₄cycloalkyl or heterocyclyl, whereinC₃₋₁₄cycloalkyl and heterocyclyl are each optionally substituted withtwo C₁₋₈alkyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted C₃₋₁₄cycloalkyl is selected from cyclopropyl;optionally substituted heterocyclyl is selected from morpholinyl or1,3,2-dioxaborolanyl; optionally substituted aryl is selected fromphenyl; or, optionally substituted heteroaryl is selected from1H-pyrazolyl.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted C₃₋₁₄cycloalkyl is selected from cyclopropyl.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted heterocyclyl is selected from morpholinyl or1,3,2-dioxaborolanyl.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted heterocyclyl is selected from morpholin-4-yl or1,3,2-dioxaborolan-2-yl.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted heterocyclyl is 1,3,2-dioxaborolanyl optionallysubstituted with one, two, three or four halo or C₁₋₈alkyl substituents.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted heterocyclyl is 1,3,2-dioxaborolan-2-yloptionally substituted with one, two, three or four halo or C₁₋₈alkylsubstituents.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted aryl is selected from phenyl.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted heteroaryl is selected from 1H-pyrazolyl.

Another embodiment includes a compound of Formula (I), wherein R₆optionally substituted heteroaryl is selected from 1H-pyrazol-1-yl.

Another embodiment includes a compound of Formula (I), wherein R₇ ishydroxyl.

Another embodiment includes a compound of Formula (I), wherein R₇ is(C₁₋₈alkoxy)_(n), wherein n represents an integer from 1 to 5.

Another embodiment includes a compound of Formula (I), wherein R₈ ishydrogen.

Another embodiment includes a compound of Formula (I), wherein R₈ isC₁₋₈alkyl.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a freeacid, free base, salt, ester, hydrate, solvate, chelate, clathrate,polymorph, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a freeacid, free base, salt, ester, hydrate, solvate, or polymorph thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a salt,ester, hydrate, solvate, chelate, clathrate, polymorph, isotopologue,stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a freeacid, free base, salt, hydrate or polymorph thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a freeacid, free base, hydrate, solvate or polymorph thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a salt,hydrate, solvate or polymorph thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a freeacid, free base or salt thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a freeacid or free base thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from a saltthereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is selected from apolymorph thereof.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is pharmaceuticallyacceptable.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the form of the compound of Formula (I) is isolated.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the compound is a compound of Formula (II), Formula (III) orFormula (IV):

or a form thereof, wherein

-   R₉ and R₁₀ are independently hydrogen, hydroxyl, C₁₋₈alkyl,    hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkyl-carbonyl,    amino-carbonyl, C₁₋₈alkyl-amino-carbonyl,    (C₁₋₈alkyl)₂-amino-carbonyl, C₁₋₈alkoxy-carbonyl, amino-sulfonyl,    C₁₋₈alkyl-amino-sulfonyl, (C₁₋₈alkyl)₂-amino-sulfonyl or P(O)(R₇)₂.

Another embodiment includes a compound of Formula (III), wherein one ofR₉ and R₁₀ is hydrogen and the other is hydroxyl, C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkyl-carbonyl,amino-carbonyl, C₁₋₈alkyl-amino-carbonyl, (C₁₋₈alkyl)₂-amino-carbonyl,C₁₋₈alkoxy-carbonyl, amino-sulfonyl, C₁₋₈alkyl-amino-sulfonyl,(C₁₋₈alkyl)₂-amino-sulfonyl or P(O)(R₇)₂.

Another embodiment includes a compound of Formula (I) or a form thereof,wherein the compound is a compound of Formula (Ia), Formula (IIa),Formula (IIIa) or Formula (IVa):

or a form thereof, wherein R₂, R₃, R₉, R₁₀ or R₁₁ are independentlydeuterium.

A compound of Formula (I) or a form thereof selected from the groupconsisting of:

wherein the form of the compound of Formula (I) is selected from a salt,ester, hydrate, solvate, chelate, clathrate, polymorph, isotopologue,stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

A compound of Formula (I) or a form thereof selected from the groupconsisting of:

Cpd Name 1 6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 2N²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4-diamine 3N²-[4-(trifluoromethyl)phenyl]-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine 46-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 5N²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 64-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine 76-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 84-chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amine 96-(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-2,4-diamine 10N²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 11N²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 126-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-2,4-diamine 13N²-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 14N²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 152-{[6-(2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol 162-{[2-{[3-fluoro-4-(trifluoromethyl)phenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol 172-{[2-{[4-(difluoromethoxy)-3-fluorophenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol 184-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine 194-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-2-amine 206-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 212-{[6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol 22N⁴-hydroxy-6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 236-(2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 246-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 256-(quinolin-4-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4- diamine26 6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 276-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 28[3-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)imidazo[1,2-a]pyridin-2-yl]methanol 29[3-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl]methanol 304-chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amine 316-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 326-(6-chloro-2-ethyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 336-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 346-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 356-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 364-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine 376-(2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine 384-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine 396-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine 406-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine 416-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 426-(2,6-dimethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 436-(2-ethyl-5-fluoro-1-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine 446-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine 456-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 466-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-ol 476-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 486-(6-fluoro-2-methylimidazo[1,2-a]pyrimidin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 49N²-[4-(difluoromethoxy)phenyl]-6-(5,7-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 506-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 51N²-[4-(difluoromethoxy)phenyl]-6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 526-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 536-(2,6-dimethyl-1H-benzimidazol-1-yl)-N²-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 54N²-[4-(difluoromethoxy)phenyl]-6-(2,6-dimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 55N²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-2,4-diamine 565-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 576-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 585-fluoro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 596-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 60N²-[4-(difluoromethoxy)phenyl]-6-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 616-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 625-fluoro-6-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 636-[2-(difluoromethyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 646-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 656-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 666-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 676-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile 686-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile 696-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 706-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 71N²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 72N²-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine 736-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 746-[2-(propan-2-yl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 753-{[4-(imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino} benzamide 76N²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 77N²-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 78N²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(methoxymethyl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine 79N²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine 806-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 81N²-[4-(difluoromethoxy)phenyl]-6-[5-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine 826-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 83N²-[4-(difluoromethoxy)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 84N²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 856-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 866-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 876-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 88N²-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine 89N²-[4-(difluoromethoxy)phenyl]-6-[2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine 906-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 91N²-[4-(difluoromethoxy)phenyl]-6-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4-diamine 926-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 936-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 94N²-[4-(difluoromethoxy)phenyl]-5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 956-(2-ethyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine 966-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 976-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 98N²-[4-(trifluoromethyl)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidine-2,4-diamine 99[6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]phosphoramidic acid 1006-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 101N²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)pyrimidine-2,4-diamine 1026-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1036-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1046-(2-ethyl-5-fluoro-1-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 105N²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1066-(2-cyclopropyl-5-methoxypyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1076-(2-cyclopropyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1086-(6-fluoro-2-methyl-4-oxido-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1096-(5-fluoro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1106-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide 1116-(2-ethyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1126-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide 1134-chloro-6-(5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine 1146-(5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 115N²-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 3-oxide 1166-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide 1173-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-2,5,6-trimethylpyrazolo[1,5-c]pyrimidin-7(6H)-one 1186-(2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide 1196-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide 1206-(5-amino-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1216-(5-chloro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 1226-(5-chloro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1236-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1246-(5-chloro-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1256-(5-chloro-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine 1266-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 1276-(2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine 1286-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 129N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 130N²-(1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 131N²-(4-bromophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1326-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine 1336-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine 1346-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 135N²-(4-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 136N²-[4-(dimethylamino)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1374-{[4-amino-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile 1386-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-fluorophenyl)pyrimidine-2,4-diamine 1396-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine 1406-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamine 141N²-(3-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 142N²-(3-fluoro-4-methoxyphenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1436-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-phenylpyrimidine-2,4-diamine 144N²-[4-(dimethylamino)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1454-{[4-amino-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile 1466-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine 147N²-(2,2-difluoro-1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 148N²-(3-fluoro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 149N²-(3-chloro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 150N²-(4-chlorophenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 151 6-(2-ethyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine 1526-(2-ethyl-1H-benzimidazol-1-yl)-N²-(2-methylphenyl)pyrimidine-2,4-diamine 1536-(2-ethyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 154N²-(1,3-benzodioxol-5-yl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1556-(2-ethyl-1H-benzimidazol-1-yl)-N²-(3-fluoro-4-methoxyphenyl)pyrimidine-2,4-diamine 156N²-(3-chloro-4-methoxyphenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 157N²-(6-methoxypyridin-3-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 158N²-(4-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1596-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-phenylpyrimidine-2,4-diamine 1606-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 1616-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine 162N²-[4-(dimethylamino)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1636-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-fluorophenyl)pyrimidine-2,4-diamine 164N²-(3-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1656-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamine 1666-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine 1674-{[4-amino-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile 1686-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-fluoro-4-methoxyphenyl)pyrimidine-2,4-diamine 1696-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(4-fluorophenyl)pyrimidine-2,4-diamine 1706-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine 1716-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 172N²-(4-chlorophenyl)-6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4-diamine 1736-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine 174N²-(4-chloro-3-fluorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 175N²-(4-chloro-3-fluorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1765-fluoro-N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 177N²-(4-chlorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1785-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 179N²-(4-chloro-3-fluorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1806-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine 1816-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 182N²-(4-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 183N²-(4-methylphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 184N²-(4-chlorophenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 185N²-(4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 186N²-(3-fluoro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 187N²-(3-chloro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 188N²-[4-(difluoromethoxy)phenyl]-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1896-(3,5-dimethyl-1,2-oxazol-4-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine 1906-(3,5-dimethyl-1,2-oxazol-4-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine 191N²-(4-chlorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 192N²-(4-chloro-3-fluorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 193N²-(3-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 1946-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine 1956-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine 1966-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamine 1975-chloro-N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 198N²-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)pyrimidine-2,4-diamine; and, 199 6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide;wherein the form of the compound of Formula (I) is selected from a salt,ester, hydrate, solvate, chelate, clathrate, polymorph, isotopologue,stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

A compound of Formula (I) or a form thereof is selected from the groupconsisting of:

Cpd Name 4a 6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine methanesulfonate 7a6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine hydrochloride 7b6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine methanesulfonate 7c6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine hydrochloride 7d6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine hydrobromide 7e6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine sulfate (2:1); and, 99a disodium [6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]phosphoramidate;wherein the form of the compound of Formula (I) is selected from a freeacid, free base, ester, hydrate, solvate, chelate, clathrate, polymorph,isotopologue, stereoisomer, racemate, enantiomer, diastereomer ortautomer thereof.Terminology

The chemical terms used above and throughout the description herein,unless specifically defined otherwise, shall be understood by one ofordinary skill in the art to have the following indicated meanings.

As used herein, the term “C₁₋₈alkyl” refers to saturated hydrocarbonradicals having from one to eight carbon atoms in a straight or branchedchain configuration, including, without limitation, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl and the like. In some embodiments, C₁₋₈alkylincludes C₁₋₆alkyl, C₁₋₄alkyl and the like. A C₁₋₈alkyl radical may beoptionally substituted where allowed by available valences.

As used herein, the term “C₂₋₈alkenyl” refers to partially unsaturatedhydrocarbon radicals having from two to eight carbon atoms in a straightor branched chain configuration and one or more carbon-carbon doublebonds therein, including, without limitation, ethenyl, allyl, propenyland the like. In some embodiments, C₂₋₈alkenyl includes C₂₋₆alkenyl,C₂₋₄alkenyl and the like. A C₂₋₈alkenyl radical may be optionallysubstituted where allowed by available valences.

As used herein, the term “C₂₋₈alkynyl” refers to partially unsaturatedhydrocarbon radicals having from two to eight carbon atoms in a straightor branched chain configuration and one or more carbon-carbon triplebonds therein, including, without limitation, ethynyl, propynyl and thelike. In some embodiments, C₂₋₈alkynyl includes C₂₋₆alkynyl, C₂₋₄alkynyland the like. A C₂₋₈alkynyl radical may be optionally substituted whereallowed by available valences.

As used herein, the term “C₁₋₈alkoxy” refers to saturated hydrocarbonradicals of from one to eight carbon atoms having a straight or branchedchain configuration of the formula: —O—C₁₋₈alkyl, including, withoutlimitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In someembodiments, C₁₋₈alkoxy includes C₁₋₆alkoxy, C₁₋₄alkoxy and the like. AC₁₋₈alkoxy radical may be optionally substituted where allowed byavailable valences.

As used herein, the term “C₃₋₁₄cycloalkyl” refers to a saturatedmonocyclic, bicyclic or polycyclic hydrocarbon radical, including,without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, 2,3-dihydro-1H-indenyl,tetrahydro-naphthalenyl and the like. In some embodiments,C₃₋₁₄cycloalkyl includes C₃₋₈cycloalkyl, C₅₋₈cycloalkyl, C₃₋₁₀cycloalkyland the like. A C₃₋₁₄cycloalkyl radical may be optionally substitutedwhere allowed by available valences.

As used herein, the term “aryl” refers to a monocyclic, bicyclic orpolycyclic aromatic carbon atom ring structure radical, including,without limitation, phenyl, naphthyl (also referred to as naphthalenyl),anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An arylradical may be optionally substituted where allowed by availablevalences.

As used herein, the term “heteroaryl” refers to a monocyclic, bicyclicor polycyclic aromatic carbon atom ring structure radical in which oneor more carbon atom ring members have been replaced, where allowed bystructural stability, with one or more heteroatoms, such as an O, S or Natom, including, without limitation, furanyl, thienyl (also referred toas thiophenyl), pyrrolyl, pyrazolyl (also referred to as 1H-pyrazolyl),imidazolyl (also referred to as 1H-imidazolyl), isoxazolyl (alsoreferred to as 1,2-oxazolyl), isothiazolyl, oxazolyl, thiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl,pyridinyl (also referred to as pyridyl), pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, indolyl (also referred to as 1H-indolyl),azaindolyl, indazolyl (also referred to as 2H-indazolyl), azaindazolyl,isoindolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl(also referred to as 1H-benzimidazolyl), benzothiazolyl, benzoxazolyl,imidazo[2,1-b][1,3]thiazolyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-c]pyrimidinyl, imidazo[1,2-a]pyridinyl,1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl,imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 7H-purinyl,9H-purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,acridinyl and the like and associated homologs and regioisomers thereof.A heteroaryl radical may be optionally substituted on a carbon ornitrogen atom ring member where allowed by available valences.

As used herein, the term “heterocyclyl” refers to a saturated orpartially unsaturated monocyclic, bicyclic or polycyclic carbon atomring structure radical in which one or more carbon atom ring membershave been replaced, where allowed by structural stability, with aheteroatom, such as an O, S or N atom, including, without limitation,oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl,dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl,dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl,imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl,isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl,thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl,oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl,tetrazolidinyl, 1,3-dioxolanyl, dihydro-2H-pyranyl,tetrahydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl,dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, dihydro-pyrazinyl,tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl,piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl,1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl,dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl,dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,tetrahydro-benzothienyl, dihydro-benzoimidazolyl,tetrahydro-benzoimidazolyl, dihydro-benzooxazolyl,tetrahydro-benzooxazolyl, dihydro-benzooxazinyl,tetrahydro-benzooxazinyl, benzo[1,3]dioxolyl (also referred to as1,3-benzodioxolyl), benzo[1,4]dioxanyl (also referred to as1,4-benzodioxanyl or 2,3-dihydro-1,4-benzodioxinyl), benzo[1,4]dioxinyl(also referred to as 1,4-benzodioxinyl),4,5,6,7-tetrahydro-2H-indazolyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, dihydro-purinyl,tetrahydro-purinyl, dihydro-quinolinyl, tetrahydro-quinolinyl,dihydro-isoquinolinyl, tetrahydro-isoquinolinyl, dihydro-quinazolinyl,tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyland the like and associated homologs thereof. A heterocyclyl radical maybe optionally substituted on a carbon or nitrogen atom ring member whereallowed by available valences.

As used herein, the term “B(OR₈)₂” refers to a radical of the formula:—B[(—OH)(—OH)] when R₈ is hydrogen; or, —[(—OH)(—O—C₁₋₈alkyl)] when R₈is independently hydrogen or C₁₋₈alkyl; or,—B[(—O—C₁₋₈alkyl)(-O—C₁₋₈alkyl)] when R₈ is C₁₋₈alkyl; or, aheterocyclyl ring system when C₁₋₈alkyl optionally forms a heterocyclylring with the oxygen atoms of attachment.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-C₂₋₈alkenyl” refers to a radical ofthe formula: —C₂₋₈alkenyl-O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-C₂₋₈alkynyl” refers to a radical ofthe formula: —C₂₋₈alkynyl-O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl” refers to a radical ofthe formula: —C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl-amino” refers to a radicalof the formula: —NH—C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl-amino-C₁₋₈alkyl” refers toa radical of the formula: —C₁₋₈alkyl-NH—C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-imino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl(═N—O—C₁₋₈alkyl).

As used herein, the term “C₁₋₈alkyl-amino” refers to a radical of theformula: —NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino” refers to a radical of theformula: —N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino” refers toa radical of the formula: —NH—C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-carbonyl” refers to a radicalof the formula: —C(O)—NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-carbonyl” refers to aradical of the formula: —C(O)—N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-carbonyl-amino” refers to aradical of the formula: —NH—C(O)—NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-carbonyl-amino” refers to aradical of the formula: —NH—C(O)—N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-sulfonyl” refers to a radicalof the formula: —SO₂—NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-sulfonyl” refers to aradical of the formula: —SO₂—N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-sulfonyl-amino” refers to aradical of the formula: —NH—SO₂—NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-sulfonyl-amino” refers to aradical of the formula: —NH—SO₂—N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-carbonyl” refers to a radical of theformula: —C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-carbonyl-amino” refers to a radicalof the formula: —NH—C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-carbonyl-amino-C₁₋₈alkyl” refers toa radical of the formula: —C₁₋₈alkyl-C(O)—NH—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-carbonyl-oxy” refers to a radical ofthe formula: —O—C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-O—C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-sulfonyl” refers to a radical of theformula: —SO₂—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-thio” refers to a radical of theformula: —S—C₁₋₈alkyl.

As used herein, the term “amino” refers to a radical of the formula:—NH₂.

As used herein, the term “amino-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-NH₂.

As used herein, the term “amino-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-NH₂.

As used herein, the term “amino-carbonyl” refers to a radical of theformula: —C(O)—NH₂.

As used herein, the term “amino-carbonyl-amino” refers to a radical ofthe formula: —NH—C(O)—NH₂.

As used herein, the term “amino-sulfonyl” refers to a radical of theformula: —SO₂—NH₂.

As used herein, the term “amino-sulfonyl-amino” refers to a radical ofthe formula: —NH—SO₂—NH₂.

As used herein, the term “aryl-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-aryl.

As used herein, the term “aryl-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-aryl.

As used herein, the term “aryl-amino” refers to a radical of theformula: —NH-aryl.

As used herein, the term “carboxyl” refers to a radical of the formula:—COOH, —C(O)OH or —CO₂H.

As used herein, the term “formyl” refers to a radical of the formula:—C(O)—H.

As used herein, the term “formyl-oxy” refers to a radical of theformula: —O—C(O)—H.

As used herein, the term “halo” or “halogen” refers to a halogen atomradical, including fluoro, chloro, bromo and iodo.

As used herein, the term “halo-C₁₋₈alkoxy” refers to a radical of theformula: —O—C₁₋₈alkyl-halo, wherein C₁₋₈alkyl may be partially orcompletely substituted where allowed by available valences with one ormore halogen atoms. In some embodiments, halo-C₁₋₈alkoxy includeshalo-C₁₋₆alkoxy, halo-C₁₋₄alkoxy and the like.

As used herein, the term “halo-C₁₋₈alkoxy-carbonyl” refers to a radicalof the formula: —C(O)—O—C₁₋₈alkyl-halo.

As used herein, the term “halo-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-halo, wherein C₁₋₈alkyl may be partially orcompletely substituted where allowed by available valences with one ormore halogen atoms. In some embodiments, halo-C₁₋₈alkyl includeshalo-C₁₋₆alkyl, halo-C₁₋₄alkyl and the like.

As used herein, the term “halo-C₁₋₈alkyl-carbonyl” refers to a radicalof the formula: —C(O)—C₁₋₈alkyl-halo.

As used herein, the term “halo-C₁₋₈alkyl-sulfonyl” refers to a radicalof the formula: —SO₂—C₁₋₈alkyl-halo.

As used herein, the term “halo-C₁₋₈alkyl-thio” refers to a radical ofthe formula: —S—C₁₋₈alkyl-halo.

As used herein, the term “heteroaryl-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-heteroaryl.

As used herein, the term “hydroxyl-C₁₋₈alkoxy” refers to a radical ofthe formula: —O—C₁₋₈alkyl-OH, wherein C₁₋₈alkyl may be partially orcompletely substituted where allowed by available valences with one ormore hydroxyl radicals.

As used herein, the term “hydroxyl-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-OH, wherein C₁₋₈alkyl may be partially or completelysubstituted where allowed by available valences with one or morehydroxyl radicals.

As used herein, the term “hydroxyl-amino” refers to a radical of theformula: —NH—OH.

As used herein, the term “hydroxyl-C₁₋₈alkyl-amino” refers to a radicalof the formula: —NH—C₁₋₈alkyl-OH.

As used herein, the term “hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl” refers toa radical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino”refers to a radical of the formula: —NH—C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “hydroxyl-imino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl(═N—OH).

As used herein, the term “imino” refers to a radical of the formula:═NH.

As used herein, the term “imino-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl(═NH).

As used herein, the term “N-oxide” refers to a moiety of the formula:

As used herein, the term “oxo” refers to a moiety of the formula:

As used herein, the term “P(O)(R₇)₂-amino” refers to a radical of theformulae: —NH—P(O)(—O—C₁₋₈alkyl)(OH) when R₇ is independently hydroxyland (C₁₋₈alkoxy)_(n), where n is 1; or, —NH—P(O)(OH)₂ when R₇ ishydroxyl; or, —NH—P(O)(—O—C₁₋₈alkyl)₂ when R₇ is (C₁₋₈alkoxy)_(n), wheren is 1.

As used herein, the term “substituent” means positional variables on theatoms of a core molecule that are attached at a designated atomposition, replacing one or more hydrogen atoms on the designated atom,provided that the atom of attachment does not exceed the availablevalence or shared valence, such that the substitution results in astable compound. Accordingly, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds. Any carbon atom as well as heteroatom with a valence levelthat appears to be unsatisfied as described or shown herein is assumedto have a sufficient number of hydrogen atom(s) to satisfy the valencesdescribed or shown.

As used herein, the term “and the like,” with reference to thedefinitions of chemical terms provided herein, means that variations inchemical structures that could be expected by one skilled in the artinclude, without limitation, isomers (including chain, branching orpositional structural isomers), hydration of ring systems (includingsaturation or partial unsaturation of monocyclic, bicyclic or polycyclicring structures) and all other variations where allowed by availablevalences which result in a stable compound.

For the purposes of this description, where one or more substituentvariables for a compound of Formula (I) encompass functionalitiesincorporated into a compound of Formula (I), each functionalityappearing at any location within the disclosed compound may beindependently selected, and as appropriate, independently and/oroptionally substituted.

As used herein, the terms “independently selected,” or “each selected”refer to functional variables in a substituent list that may be attachedmore than once on the structure of a core molecule, where the pattern ofsubstitution at each occurrence is independent of the pattern at anyother occurrence. Further, the use of a generic substituent variable ona core structure for a compound described herein is understood toinclude the replacement of the generic substituent with speciesubstituents that are included within the particular genus, e.g., arylmay be replaced with phenyl or naphthalenyl and the like, such that theresulting compound is to be included within the scope of the compoundsdescribed herein.

As used herein, the term “optionally substituted” means that thespecified substituent variables, groups, radicals or moieties representthe scope of the genus and may be independently chosen as needed toreplace one or more hydrogen atoms on the designated atom of attachmentof a core molecule.

As used herein, the terms “stable compound” or “stable structure” mean acompound that is sufficiently robust to be isolated to a useful degreeof purity from a reaction mixture and formulations thereof into anefficacious therapeutic agent.

Compound names used herein were obtained using the ACD Labs Index Namesoftware provided by ACD Labs and/or ChemDraw Ultra software provided byCambridgeSoft. When the compound name disclosed herein conflicts withthe structure depicted, the structure shown will supercede the use ofthe name to define the compound intended.

Compound Forms

As used herein, the terms a “compound of Formula (Ia),” “a compound ofFormula (II),” “compound of Formula (IIa),” “compound of Formula (III),”“compound of Formula (IIIa),” “compound of Formula (IV)” or “compound ofFormula (IVa)” refer to subgenera of the compound of Formula (I) or aform thereof, as defined herein. Rather than repeat the varioussubgenera of the compound of Formula (I), in certain embodiments, theterm “a compound(s) of Formula (I) or a form thereof” is usedinclusively to refer to compound(s) of Formula (Ia) or a form thereof,compound(s) of Formula (II) or a form thereof, compound(s) of Formula(IIa) or a form thereof, compound(s) of Formula (III) or a form thereof,compound(s) of Formula (IIIa) or a form thereof, compound(s) of Formula(IV) or a form thereof or compound(s) of Formula (IVa) or a formthereof, either separately or together. Thus, embodiments and referencesto “a compound of Formula (I)” are intended to be inclusive of compoundsof Formula (Ia), compounds of Formula (II), compounds of Formula (IIa),compounds of Formula (III), compounds of Formula (IIIa), compounds ofFormula (IV) and compounds of Formula (IVa).

As used herein, the term “form” means a compound of Formula (I) selectedfrom a free acid, free base, salt, ester, hydrate, solvate, chelate,clathrate, polymorph, isotopologue, stereoisomer, racemate, enantiomer,diastereomer, or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is selected from a salt, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is selected from a free acid, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is selected from a free base, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a free acid, free base or salt thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is an isotopologue thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a stereoisomer, racemate, enantiomer or diastereomerthereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a pharmaceutically acceptable form.

In certain embodiments described herein, the compound of Formula (I) ora form thereof is isolated for use.

As used herein, the term “isolated” means the physical state of acompound of Formula (I) or a form thereof after being isolated and/orseparated and/or purified from a synthetic process (e.g., from areaction mixture) or natural source or combination thereof according toan isolation, separation or purification process or processes describedherein or which are well known to the skilled artisan (e.g.,chromatography, recrystallization and the like) in sufficient purity tobe characterizable by standard analytical techniques described herein orwell known to the skilled artisan.

As used herein, the term “protected” means that a functional group on acompound of Formula (I) or a form thereof is in a form modified topreclude undesired side reactions of the functional group when thecompound is subjected to a reaction. Suitable protecting groups will berecognized by those with ordinary skill in the art as well as byreference to standard textbooks such as, for example, T. W. Greene etal, Protective Groups in Organic Synthesis (2007), Wiley, New York.

Prodrugs and solvates of the compounds of Formula (I) or a form thereofdescribed herein are also contemplated.

As used herein, the term “prodrug” means that a functional group on acompound of Formula (I) is in a form (e.g., acting as an active orinactive drug precursor) that is transformed in vivo to yield an activeor more active compound of Formula (I) or a form thereof. Thetransformation may occur by various mechanisms (e.g., by metabolicand/or non-metabolic chemical processes), such as, for example, byhydrolysis and/or metabolism in blood, liver and/or other organs andtissues. A discussion of the use of prodrugs is provided by V. J.Stella, et. al., “Biotechnology: Pharmaceutical Aspects, Prodrugs:Challenges and Rewards,” American Association of PharmaceuticalScientists and Springer Press, 2007.

In one example, when a compound of Formula (I) or a form thereofcontains a carboxylic acid functional group, a prodrug can comprise anester formed by the replacement of the hydrogen atom of the acid groupwith a functional group such as alkyl and the like. In another example,when a compound of Formula (I) or a form thereof contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a functional group such as alkylor carbonyloxy and the like. In another example, when a compound ofFormula (I) or a form thereof contains an amine functional group, aprodrug can be formed by the replacement of one or more amine hydrogenatoms with a functional group such as alkyl or substituted carbonyl.

Pharmaceutically acceptable prodrugs of compounds of Formula (I) or aform thereof include those compounds substituted with one or more of thefollowing groups: carboxylic acid esters (e.g., via carboxylic acid usedto derive a carboxylate ester further substituted with alkyl), sulfonateesters, amino acid esters or phosphonate esters (e.g., viaphosphoramidic acid used to derive a phosphoramidate mono-, di- ortriphosphate ester further substituted with alkyl). As described herein,it is understood by a person of ordinary skill in the art that one ormore of such substituents may be used to provide a compound of Formula(I) or a form thereof as a prodrug.

The compounds of Formula (I) or a form thereof can form salts, which areintended to be included within the scope of this description. Referenceto a compound of Formula (I) or a form thereof herein is understood toinclude reference to salts thereof, unless otherwise indicated. The term“salt(s)”, as employed herein, denotes acidic salts formed withinorganic and/or organic acids, as well as basic salts formed withinorganic and/or organic bases. In addition, when a compound of Formula(I) or a form thereof contains both a basic moiety, such as, but notlimited to a pyridine or imidazole, and an acidic moiety, such as, butnot limited to a carboxylic acid, zwitterions (“inner salts”) may beformed and are included within the term “salt(s)” as used herein.

The term “pharmaceutically acceptable salt(s)”, as used herein, meansthose salts of compounds of Formula (I) or a form thereof describedherein that are safe and effective (i.e., non-toxic, physiologicallyacceptable) for use in mammals and that possess biological activity,although other salts are also useful. Salts of the compounds of theFormula (I) or a form thereof may be formed, for example, by reacting acompound of Formula (I) or a form thereof with an amount of acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic orbasic groups present in compounds of Formula (I) or a form thereofdescribed herein. Embodiments of acid addition salts include, and arenot limited to, acetate, acid phosphate, ascorbate, benzoate,benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride,citrate, camphorate, camphorsulfonate, ethanesulfonate, formate,fumarate, gentisinate, gluconate, glucaronate, glutamate, hydrobromide,hydrochloride, dihydrochloride, hydroiodide, isonicotinate, lactate,maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate,pamoate, pantothenate, phosphate, propionate, saccharate, salicylate,succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also knownas tosylate), trifluoroacetate, trifluoroacetic acid salt and the like.One or more embodiments of acid addition salts include chloride,hydrochloride, dihydrochloride, trihydrochloride, hydrobromide, acetate,diacetate, methanesulfonate, sulfate, trifluoroacetate, trifluoroaceticacid salt and the like. More particular embodiments include a chloride,hydrochloride, dihydrochloride, hydrobromide, methanesulfonate, sulfate,trifluoroacetate, trifluoroacetic acid salt and the like.

In certain embodiments of the compounds of Formula (I) or a form thereofdescribed herein, the compound is isolated as a salt form, wherein thecompound is conjugated with the salt in a ratio represented as, in anon-limiting example, “compound:salt (A:B),” wherein “A” and “B”represent the equivalents of compound to salt in the isolated form.

Additionally, acids which are considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33,201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Suitable basic salts include, but are not limited to, aluminum,ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts. Certain compounds of Formula (I) or a form thereofdescribed herein can also form pharmaceutically acceptable salts withorganic bases (for example, organic amines) such as, but not limited to,dicyclohexylamines, tert-butyl amines and the like, and with variousamino acids such as, but not limited to, arginine, lysine and the like.Basic nitrogen-containing groups may be quarternized with agents such aslower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromidesand iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be included withinthe scope of pharmaceutically acceptable salts as described herein. Inaddition, all such acid and base salts are considered equivalent to thefree forms of the corresponding compounds of Formula (I) or a formthereof for purposes of this description.

Compounds of Formula (I), and forms thereof, may further exist in atautomeric form. All such tautomeric forms are contemplated and intendedto be included within the scope of the compounds of Formula (I) or aform thereof as described herein.

The compounds of Formula (I) or a form thereof may contain asymmetric orchiral centers, and, therefore, may exist in different stereoisomericforms. The present description is intended to include all stereoisomericforms of the compounds of Formula (I) as well as mixtures thereof,including racemic mixtures.

The compounds of Formula (I) or a form thereof described herein mayinclude one or more chiral centers, and as such may exist as racemicmixtures (R/S) or as substantially pure enantiomers and diastereomers.The compounds of Formula (I) or a form thereof may also exist assubstantially pure (R) or (S) enantiomers (when one chiral center ispresent). In one embodiment, the compounds of Formula (I) or a formthereof described herein are (S) isomers and may exist asenantiomerically pure compositions substantially comprising only the (S)isomer. In another embodiment, the compounds of Formula (I) or a formthereof described herein are (R) isomers and may exist asenantiomerically pure compositions substantially comprising only the (R)isomer. As one of skill in the art will recognize, when more than onechiral center is present, the compounds of Formula (I) or a form thereofdescribed herein may also exist as a (R,R), (R,S), (S,R) or (S,S)isomer, as defined by IUPAC Nomenclature Recommendations.

As used herein, the term “substantially pure” refers to compounds ofFormula (I) or a form thereof consisting substantially of a singleisomer in an amount greater than or equal to 90%, in an amount greaterthan or equal to 92%, in an amount greater than or equal to 95%, in anamount greater than or equal to 98%, in an amount greater than or equalto 99%, or in an amount equal to 100% of the single isomer.

In one aspect of the description, a compound of Formula (I) or a formthereof is a substantially pure (S) enantiomer present in an amountgreater than or equal to 90%, in an amount greater than or equal to 92%,in an amount greater than or equal to 95%, in an amount greater than orequal to 98%, in an amount greater than or equal to 99%, or in an amountequal to 100%.

In one aspect of the description, a compound of Formula (I) or a formthereof is a substantially pure (R) enantiomer present in an amountgreater than or equal to 90%, in an amount greater than or equal to 92%,in an amount greater than or equal to 95%, in an amount greater than orequal to 98%, in an amount greater than or equal to 99%, or in an amountequal to 100%.

As used herein, the term “racemate” refers to any mixture of isometricforms that are not “enantiomerically pure”, including mixtures such as,without limitation, in a ratio of about 50/50, about 60/40, about 70/30,about 80/20, about 85/15 or about 90/10.

In addition, the compounds of Formula (I) or a form thereof describedherein embrace all geometric and positional isomers. For example, if acompound of Formula (I) or a form thereof incorporates a double bond ora fused ring, both the cis- and trans-forms, as well as mixturesthereof, are embraced within the scope of the compounds of Formula (I)or a form thereof described herein.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by use of a chiral HPLC column or other chromatographicmethods known to those skilled in the art.

Enantiomers can also be separated by converting the enantiomeric mixtureinto a diastereomeric mixture by reaction with an appropriate opticallyactive compound (e.g., chiral auxiliary such as a chiral alcohol orMosher's acid chloride), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereomers to the correspondingpure enantiomers.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds of Formula (I) or a form thereof(including salts, solvates, esters and prodrugs and transformed prodrugsthereof), which may exist due to asymmetric carbons on varioussubstituents, including enantiomeric forms (which may exist even in theabsence of asymmetric carbons), rotameric forms, atropisomers,diastereomeric and regioisomeric forms, are contemplated within thescope of the description herein. Individual stereoisomers of thecompounds of Formula (I) or a form thereof described herein may, forexample, be substantially free of other isomers, or may be present in aracemic mixture, as described supra.

The use of the terms “salt,” “solvate,” “ester,” “prodrug” and the like,is intended to apply equally to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates, isotopologues or prodrugs of the instant compounds.

The term “isotopologue” refers to isotopically-enriched compounds ofFormula (I) or a form thereof which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number found in nature. Examples of isotopes that can beincorporated into compounds of Formula (I) or a form thereof describedherein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as H², H³, C¹³, C¹⁴, N¹⁵, O¹⁸,O¹⁷, P³¹, P³², S³⁵, F¹⁸, Cl³⁵ and Cl³⁶, respectively, each of which isalso within the scope of this description.

Certain isotopically-enriched forms of compounds of Formula (I) or aform thereof described herein (e.g., those labeled with H³ and C¹⁴) areuseful in compound and/or substrate tissue distribution assays.Tritiated (i.e. H³) and carbon-14 (i.e., C¹⁴) isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium (i.e., “deuteriumenriched”) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life),increased solubility, reduced dosage requirements (e.g., increasedbioavailability) or reduced toxicity (e.g., reduced inhibition ofmetabolic enzymes) and hence may be preferred in some circumstances.

One or more compounds of Formula (I) or a form thereof described hereinmay exist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like, and thedescription herein is intended to embrace both solvated and unsolvatedforms.

As used herein, the term “solvate” means a physical association of acompound of Formula (I) or a form thereof described herein with one ormore solvent molecules. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. As used herein, “solvate” encompassesboth solution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

One or more compounds of Formula (I) or a form thereof described hereinmay optionally be converted to a solvate. Preparation of solvates isknown. A typical, non-limiting process involves dissolving a compound ofFormula (I) or a form thereof in a desired amount of the desired solvent(organic or water or mixtures thereof) at a higher than ambienttemperature, and cooling the solution at a rate sufficient to formcrystals which are then isolated by standard methods. Analyticaltechniques such as, for example infrared spectroscopy, differentialscanning calorimetry, thermogravimetric analysis, Karl-Fischer and thelike, may show the presence of the solvent (or water) in the crystals asa solvate (or hydrate).

As used herein, the term “hydrate” means a solvate wherein the solventmolecule is water.

Polymorphic crystalline and amorphous forms of the compounds of Formula(I) or a form thereof, and of the salts, solvates, esters and prodrugsof the compounds of Formula (I) or a form thereof, are further intendedto be included in the scope of the compounds of Formula (I) or a formthereof described herein.

Compound Uses

The Bmi-1 oncogene was first identified as part of a keyinsertion/activation region of the Moloney murine leukemia virus in theearly 1990's (1-6). Bmi-1 is a member of the Polycomb group (PcG) oftranscriptional repressors and was identified as a necessary regulatorof hematopoietic stem cell (HSC) self-renewal (76, 77). Park found thatBmi-1 is highly expressed in purified mouse and human HSCs and that theabsence of Bmi-1, as demonstrated by Bmi-1 knockout mice, results in theprogressive loss of all hematopoietic lineages (76). Furthermore, thetransplantation of Bmi-1^(−/−) day 14.5 fetal liver cells into lethallyirradiated normal mice, demonstrated that the cells were unable toreconstitute myeloid cells, B cells, and T-cells because Bmi-1^(−/−)HSCs were unable to renew (76).

In addition to the role of Bmi-1 in HSC self renewal, it was found thatBmi-1 transgene expression induced lymphoma in mice (2). Bmi-1 was alsofound to be overexpressed in many tumor types, including acute myeloidleukemia, medulloblastoma, neuroblastoma, colorectal cancer, lungcancer, and prostate cancer, and was found to increase with malignancy(34, 78, 61, 79, 80, 65, 43). Loss of Bmi-1 in various human cancer celllines via Bmi-1 specific RNA interference (RNAi) was shown to lead toacute cell death and growth inhibition, whereas loss of Bmi-1 in variousnormal cell lines was shown to lead to only moderate growth inhibitionand not significant cell death (69). Thus, Bmi-1 is necessary for thesurvival of cancer cells but has minimal effect on the survival ofnormal cells.

Bmi-1 has been subsequently shown to act as an oncogene experimentallyand has proven particularly potent in conjunction with c-myc to initiatelymphoma in mice (7, 8). The role of Bmi-1 in lymphomagenesis has beenattributed partially to transcriptional repression of the INK4a locus(containing both the p16^(INK4A) and p14^(ARF) genes) leading tomaintenance of cancer and tumor cell proliferation and prevention ofdifferentiation (7, 9). Loss of expression of the INK4a locus due topromoter silencing has been extensively studied and is both importantfor the progression and prognosis of many types of hematologic cancers(10, 11). The INK4a locus is occasionally lost by deletion in leukemiaand lymphoma (12, 13).

However, Bmi-1 has been shown to play a role in tumorigenesis in modelslacking the INK4a locus, indicating that other loci important in cancerare regulated by this protein (14). Experimental results havedemonstrated further that loss of Bmi-1 induces growth arrest andsenescence in fibrosarcoma cells known to lack INK4a (15). There is alsoevidence that Bmi-1 is important for the hedgehog (Hh) pathway in breastcancer. Activation of Hh signaling increases Bmi-1 expression, whiledown-regulation of Bmi-1 (via siRNA) abrogates the effects of Hhsignaling on mammosphere formation in vitro and inhibits ductal/alveolardevelopment in mice (16). Recent work has demonstrated the role of Bmi-1in the regulation of Hox gene expression. Knockdown of Bmi-1 caused aglobal and loci-specific loss of H2A ubiquitination, upregulation of theHoxCS gene, and inhibition of the growth of HeLa cells (17). Anotherstudy demonstrated that E2F6 and Bmi-1 cooperate in the regulation ofHox gene expression (particularly Hox C10 and B9), and consequentlyaffect axial skeleton development, but not in the repression of theInk4a-Arf locus. These findings underscore the significance of theE2F6-Bmi-1 interaction and suggest that the Hox and Ink4a-Arf loci areregulated by somewhat different Bmi-1-dependent mechanisms (18). Currentresearch suggests that Bmi-1 has different roles dependent upon celltypes and/or developmental stages. Other genes regulated by Bmi-1 remainto be identified.

Bmi-1 is found to be highly expressed in malignancies, such as diffuselarge B cell lymphomas (DLBCL), B cell non-Hodgkin's lymphoma, Hodgkin'slymphoma, acute myeloid leukemia, colorectal carcinoma, liver carcinoma,non-small cell lung cancer, breast carcinoma and medulloblastoma. Thestudy of Bmi-1 knockout mice has revealed that Bmi-1 is required for theself-renewal of both leukemic and normal hematopoietic stem cells.

Additionally, evidence exists linking Bmi-1 levels to blood tumor types,particularly Burkitt's lymphoma, mantle cell lymphoma, Hodgkin'slymphoma (21-23), non-Hodgkin's lymphoma, some T-cell lymphomas (2,24-31), acute myeloid leukemia and T-ALL (32-35). Raaphorst et alobserved that, in Hodgkin's lymphoma, Reed-Sternberg cells (HRS)co-express Bmi-1, EZH2, and Mib-1/Ki-67. Because HRS cells are thoughtto originate from germinal center lymphocytes that express Bmi-1, suchlymphocytes should lose the ability to express Bmi-1 (and gain theability to express EZH2) as they differentiate. These observationssuggest that Hodgkin's lymphoma is associated with aberrantco-expression of Bmi-1 and EZH2 in these cells (22). An assessment ofacute myeloid leukemia stem cell populations by van Gosliga et al (36)showed that CD34⁺/CD38⁻ cells capable of forming leukemic-cobblestonecolonies on a bone marrow substrate through at least two rounds ofexpansion represented an extreme minority of the cell population.Further analysis showed that this cell population expresses high levelsof Bmi-1 mRNA and can establish an aggressive leukemia in mice, whilethose cells that have lower levels of Bmi-1 mRNA cannot (36). Suchstudies implicate Bmi-1 in tumor growth and cell survival and suggest acentral function in tumor initiation and maintenance of tumor stemcells.

The levels of Bmi-1 have been shown to have prognostic relevance in anumber of tumor types. An example of this is found in acute myeloidleukemia based on results from a study assessing the prognostic value ofhigh Bmi-1 levels in 64 patients (32). On the basis of the median valueof Bmi-1 (54.58%), patients were divided into two groups and monitoredfor survival. Patients with lower Bmi-1 positivity (<55%, n=33) hadsignificantly longer overall survival (P=0.0001), relapse-free survival(P=0.0072) and remission duration (P=0.0065) when compared to thepatients with higher levels of Bmi-1 (>55%, n=31, respectively),regardless of age group (32). Similarly, Van Galen et al (37) have shownthat Bmi-1 levels are highly prognostic in diffuse large B celllymphomas (DLBCL) (37). Neoplastic cells in DLBCL cases originate fromgerminal centre B (GCB) cells or their descendents(38). Recentmicroarray analyses have shown that some DLBCL phenotypically resemblenon-neoplastic GCB cells, while some show an expression profile similarto that of activated B cells (ABC) (39).

Furthermore, patients with a GCB-like phenotype have a considerablybetter prognosis than those with an ABC-like phenotype (40). Bmi-1 wasidentified as one of the genes that distinguish the ABC-like DLBCL(39),(41). Other groups have linked elevated Bmi-1 levels with poorprognosis in mantle cell lymphoma (MCL), non-Hodgkin's lymphoma andother leukemias (22, 26, 27, 29, 42-44), as well as many other tumortypes including neuroblastoma, glioblastoma, hepatocellular carcinoma,and breast, colorectal, prostate, lung, gastric and salivary glandcancers (45-57). The loss of expression from the INK4a locus has alsobeen shown to have prognostic value (12, 13). Taken together, these datastrongly implicate Bmi-1 in cancer and suggest that inhibitinguncontrolled cell proliferation by inhibiting Bmi-1 function andreducing the level of Bmi-1 in a cancer cell, tumor cell, cancer stemcell or tumor stem cell will have a beneficial therapeutic effect inpatients with multiple cancer types, particularly in those afflictedwith hematological cancers.

For example, MCL is a rare, aggressive and incurable B cellnon-Hodgkin's lymphoma that is refractory (i.e., resistant toconventional chemotherapy) and is associated with a poor prognosis. MCLis characterized by the t(11;14)(q13;q32) translocation, resulting inamplification and overexpression of the polycomb group gene Bmi-1, whichnormally functions for self-renewal of hematopoietic stem cells but hasthe capacity to induce tumors when overexpressed.

Multiple myeloma is another fatal B-cell malignancy characterized by theaccumulation of abnormal plasma cells in the bone marrow. Standardtherapy for multiple myeloma is similar to the course for MCL andnormally consists of combination chemotherapy that often results in a60-70% response rate. However, most patients will eventually relapse,leaving patients with limited therapeutic options. Recent geneexpression profiling of multiple myeloma cells revealed elevatedexpression of Bmi-1 compared to that in normal plasma cells, asconfirmed by immunoblotting.

Bmi-1 has been shown to be regulated transcriptionally by a number offactors including SALL4, FoxM1, c-Myc, E2F-1 and Mel18. Bmi-1 and SALL4are putative oncogenes that modulate stem cell pluripotency and play arole in leukemigenesis (also referred to as leukemogenesis). MurineSal14 also has been shown to play an essential role in maintaining theproperties of ES (embryonic stem) cells and governing the fate of theprimitive inner cell mass. Yang et al demonstrated that transcriptionfrom the Bmi-1 promoter is markedly activated by SALL4 in adose-dependent manner (35). The Forkhead box transcription factor FoxM1is expressed in proliferating cells and has been shown to upregulate thelevels of Bmi-1 in transformed NIH 3T3 cells in response to oxidativestress through c-Myc activation (58). The Bmi-1 homologue, Mel18, actsas a potent repressor on the expression of Bmi-1. The Bmi-1 promoterregion contains a functional E-box through which c-Myc and Mel-18 canregulate Bmi-1 expression. Since Mel18 downregulates c-Myc expressionand Bmi-1 is a c-Myc target, these data suggest that Mel18 regulatesexpression of Bmi-1 via repression of c-Myc during cellular senescenceand, thus, link c-Myc and polycomb function (59). Similarly, a recentreport suggests that E2F-1 may also regulate the levels of Bmi-1 inneuroblastoma (60). The Bmi-1 promoter contains a putative E2F bindingsite required for the activation of a Bmi-1 promoter-dependent reporterconstruct by E2F-1. Neither post-transcriptional nor post-translationalcontrol of Bmi-1 production has been reported.

Without being limited by theory, the compounds of Formula (I) or a formthereof described herein may play a role in activating the apoptoticpathway as determined by annexin-V expression, as well as cleavage ofpoly (ADP-ribose) polymerase (PARP) and caspase-9 and caspase-7. Cellcycle analyses of cells treated with these compounds of Formula (I) or aform thereof have further demonstrated a block at the G₂/M phasefollowed by the development of polyploidy. These findings suggest thatBmi-1 may also play a role in DNA repair and/or regulation of mitosis.The compounds of Formula (I) or a form thereof described herein areuseful inhibitors of Bmi-1 function, causing a reduction in the level ofBmi-1 protein and are thus potential therapeutics for any cancer cell,tumor cell, cancer stem cell or tumor stem cell that overexpressesBmi-1. Additionally, the compounds of Formula (I) or a form thereofdescribed herein inhibit the function of Bmi-1 and reduce Bmi-1 levelsin cancer stem cell and tumor stem cell environments and are thus usefulin targeting cancer cell populations that have been shown to beresistant to current therapies (e.g., such as those using large andsmall molecule chemotherapeutic agents and/or radiation therapies, aswell as targeted therapies that primarily function by indiscriminatelydamaging mitotic cells).

As used herein, the italicized form of “Bmi-1,” unless otherwisespecified or clear from the context of the specification, refers to theBmi-1 gene. The nonitalicized form of “Bmi-1,” the capitalized form of“BMI-1” or the term “Bmi-1 protein,” unless otherwise specified or clearfrom the context of the specification, collectively refer to Bmi-1protein.

As used herein, the term “Bmi-1 inhibitor” or the phrase (or variationsthereof) “inhibit Bmi-1 function and reduce the level of Bmi-1” refer topost-translational inhibition of the function of Bmi-1 protein andsubsequent degradation, resulting in decreased levels of Bmi-1 proteinpresent in a tumor environment including, but not limited to, in vitroand in vivo environments comprising cancer stem cells or tumor stemcells or cancer stem cells and tumor stem cells.

In accordance with the present description, compounds of Formula (I) ora form thereof that inhibit Bmi-1 function and reduce the level of Bmi-1also inhibit proliferation of tumor cells in vitro and in vivo andenhance sensitivity of intrinsically resistant populations (e.g., either“cancer stem cells,” “tumor stem cells” or both) to chemotherapeutics.Elevated expression of human Bmi-1 has been reported in multiple cancersamples and cancer cell lines (2, 42, 51, 56, 61-68). Applicants haveidentified compounds of Formula (I) or a form thereof that inhibit Bmi-1function and reduce the level of Bmi-1 in vitro and in vivo, withconcurrent inhibition of tumor cell growth and xenograft growth in vivo.

One embodiment described herein is directed to a method of inhibitingBmi-1 function and reducing the level of Bmi-1 to treat a cancermediated by Bmi-1 in a subject in need thereof comprising contacting acell having elevated Bmi-1 levels from the subject with an amount of acompound of Formula (I) or a form thereof, wherein the cell is selectedfrom a cancer cell, tumor cell, cancer stem cell or tumor stem cell,determining an effective amount of the compound of Formula (I) or a formthereof that inhibits Bmi-1 function in the cell and subsequentlyadministering the effective amount of the compound of Formula (I) or aform thereof to the subject.

Another embodiment described herein is directed to a method ofinhibiting Bmi-1 function and reducing the level of Bmi-1 to treat acancer mediated by Bmi-1 in a subject in need thereof comprisingadministering to the subject an effective amount of the compound ofFormula (I) or a form thereof.

Another embodiment described herein is directed to a method for treatinga cancer mediated by Bmi-1 in a subject in need thereof comprisingcontacting a cell having elevated Bmi-1 levels from the subject with anamount of a compound of Formula (I) or a form thereof, wherein the cellis selected from a cancer cell, tumor cell, cancer stem cell or tumorstem cell.

Another embodiment described herein is directed to a method furthercomprising contacting a cell having elevated Bmi-1 levels from thesubject with an amount of the compound of Formula (I) or a form thereof,wherein the cell is selected from a cancer cell, tumor cell, cancer stemcell or tumor stem cell, determining an effective amount of the compoundof Formula (I) or a form thereof that inhibits Bmi-1 function in thecell and subsequently administering the effective amount of the compoundof Formula (I) or a form thereof to the subject.

Another embodiment described herein is directed to a method wherein theeffective amount of the compound of Formula (I) or a form thereofdetermined to inhibit Bmi-1 function in the contacted cell reduces Bmi-1levels in the contacted cell.

An embodiment of the method described herein comprises administering aneffective amount of a compound of Formula (I) or a form thereof toinhibit the function of Bmi-1 in a cancer cell in vivo or in vitro, in atumor cell in vivo or in vitro, in a cancer stem cell population in vivoor in vitro, or in a tumor stem population in vivo or in vitro.

An embodiment of the method described herein comprises administering aneffective amount of a compound of Formula (I) or a form thereof toreduce the level of Bmi-1 in a cancer cell in vivo or in vitro, in atumor cell in vivo or in vitro, in a cancer stem cell population in vivoor in vitro, or in a tumor stem population in vivo or in vitro.

An embodiment of the method described herein comprises administering aneffective amount of a compound of Formula (I) or a form thereof toinhibit cancer cell proliferation, tumor cell proliferation, cancer stemcell proliferation or tumor stem cell proliferation.

An embodiment described herein includes the use of a compound of Formula(I) or a form thereof in the manufacture of a medicament for inhibitingBmi-1 function and reducing the level of Bmi-1 to treat a cancermediated by Bmi-1 in a subject in need thereof comprising administeringan effective amount of the medicament to the subject.

Without being limited by theory, any type of cancer mediated by ordependent on the presence of overexpressed Bmi-1 can be treated inaccordance with the intended use of the compounds of Formula (I) or aform thereof described herein.

As used herein, the term “cancer” refers to cells in which Bmi-1 isaberrantly expressed or overexpressed and the cell depends on Bmi-1 forsurvival or proliferation. Without being limited by theory, the cellsmay be either stem-like or more differentiated, but the cell relies onBmi-1 to enable uncontrolled cell division and develop resistance tocytotoxic, chemotherapeutic agents.

In another embodiment, the term “a cancer mediated by Bmi-1” refers to acancer that is characterized by cells or a fraction of cells from acancer patient that overexpress Bmi-1 compared to cells from acancer-free patient (i.e., a patient with no detectable cancer asdetermined by conventional techniques, such as MRI, CAT scan, etc.).Alternatively, the term refers to cells or a fraction of cells from acancer patient that, relative to the cancer patient's cells fromsurrounding normal tissues, express a level of Bmi-1 that differs by atleast 2%, 4%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%. 90%, or 95% more, as detected by any methodroutinely used in the art, or described herein, e.g., in an ELISA.

Non-limiting examples of a cancer mediated by Bmi-1 that can be treatedwith the intended use described herein: leukemias, such as but notlimited to, acute leukemia, acute lymphocytic leukemia, acute myelocyticleukemias, such as, myeloblastic, promyelocytic, myelomonocytic,monocytic, and erythroleukemia leukemias and myelodysplastic syndrome;chronic leukemias, such as but not limited to, chronic myelocytic(granulocytic) leukemia, chronic lymphocytic leukemia, hairy cellleukemia; polycythemia vera; lymphomas such as but not limited toHodgkin's lymphoma, non-Hodgkin's lymphoma; multiple myelomas such asbut not limited to smoldering multiple myeloma, nonsecretory myeloma,osteosclerotic myeloma, placancer cell leukemia, solitaryplacancercytoma and extramedullary placancercytoma; Waldenström'smacroglobulinemia; monoclonal gammopathy of undetermined significance;benign monoclonal gammopathy; heavy chain disease; bone and connectivetissue sarcomas such as but not limited to bone sarcoma, osteosarcoma,chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma,rhabdomyosarcoma, synovial sarcoma; glial brain tumors (i.e., gliomas)such as but not limited to, astrocytoma, ependymoma, oligodendroglioma,brain stem glioma, optic glioma, diffuse intrinsic pontine glioma, mixedglioma (i.e., oligoastrocytoma), glioblastoma, glioblastoma multiforme,nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma,meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breastcancer including but not limited to ductal carcinoma, adenocarcinoma,lobular (cancer cell) carcinoma, intraductal carcinoma, medullary breastcancer, mucinous breast cancer, tubular breast cancer, papillary breastcancer, Paget's disease, and inflammatory breast cancer; adrenal cancersuch as but not limited to pheochromocytom and adrenocortical carcinoma;thyroid cancer such as but not limited to papillary or follicularthyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer;pancreatic cancer such as but not limited to, insulinoma, gastrinoma,glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid orislet cell tumor; pituitary cancers such as but limited to Cushing'sdisease, prolactin-secreting tumor, acromegaly, and diabetes insipius;eye cancers such as but not limited to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; vaginal cancers such as squamous cell carcinoma,adenocarcinoma, and melanoma; vulvar cancer such as squamous cellcarcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, andPaget's disease; cervical cancers such as but not limited to, squamouscell carcinoma, and adenocarcinoma; uterine cancers such as but notlimited to endometrial carcinoma and uterine sarcoma; ovarian cancerssuch as but not limited to, ovarian epithelial carcinoma, borderlinetumor, germ cell tumor, and stromal tumor; esophageal cancers such asbut not limited to, squamous cancer, adenocarcinoma, adenoid cysticcarcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma,melanoma, placancercytoma, verrucous carcinoma, and oat cell (cancercell) carcinoma; stomach cancers such as but not limited to,adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading,diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, andcarcinosarcoma; colon cancers; rectal cancers; liver cancers such as butnot limited to hepatocellular carcinoma and hepatoblastoma; gallbladdercancers such as adenocarcinoma; cholangiocarcinomas such as but notlimited to papillary, nodular, and diffuse; lung cancers such asnon-small cell lung cancer, squamous cell carcinoma (epidermoidcarcinoma), adenocarcinoma, large-cell carcinoma and small-cell lungcancer; testicular cancers such as but not limited to germinal tumor,seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma,embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sactumor), prostate cancers such as but not limited to, prostaticintraepithelial neoplasia, adenocarcinoma, leiomyosarcoma, andrhabdomyosarcoma; penal cancers; oral cancers such as but not limited tosquamous cell carcinoma; basal cancers; salivary gland cancers such asbut not limited to adenocarcinoma, mucoepidermoid carcinoma, andadenoidcystic carcinoma; pharynx cancers such as but not limited tosquamous cell cancer, and verrucous; skin cancers such as but notlimited to, basal cell carcinoma, squamous cell carcinoma and melanoma,superficial spreading melanoma, nodular melanoma, lentigo malignantmelanoma, acral lentiginous melanoma; kidney cancers such as but notlimited to renal cell carcinoma, adenocarcinoma, hypernephroma,fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer);Wilms' tumor; bladder cancers such as but not limited to transitionalcell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. Inaddition, cancers include myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma,hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogeniccarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillarycarcinoma and papillary adenocarcinomas (for a review of such disorders,see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co.,Philadelphia and Murphy et al., 1997, Informed Decisions: The CompleteBook of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin,Penguin Books U.S.A., Inc., United States of America).

The compounds of Formula (I) or a form thereof are also useful in thetreatment, prevention and/or management of a variety of cancers mediatedby Bmi-1 or other abnormal proliferative diseases (where such disease ismediated by overexpressed Bmi-1 or elevated levels of Bmi-1), including(but not limited to) the following: carcinoma, including that of thebladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach,cervix, thyroid and skin; including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Burkitt's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias andpromyelocytic leukemia; tumors of mesenchymal origin, includingfibrosarcoma and rhabdomyoscarcoma; other tumors, including melanoma,seminoma, tetratocarcinoma, neuroblastoma; tumors of the central andperipheral nervous system, including astrocytoma, neuroblastoma, glioma,and Schwannomas; tumors of mesenchymal origin, including fibrosarcoma,rhabdomyoscarama, and osteosarcoma; and other tumors, includingmelanoma, xeroderma pigmentosum, keratoactanthoma, seminoma, thyroidfollicular cancer and teratocarcinoma. In some embodiments, cancersassociated with aberrations in apoptosis are treated in accordance withthe methods described herein. Such cancers may include, but are notlimited to, follicular lymphomas, carcinomas with p53 mutations, hormonedependent tumors of the breast, prostate and ovary, and precancerouslesions such as familial adenomatous polyposis, and myelodysplasticsyndromes. In specific embodiments, malignancy or dysproliferativechanges (such as metaplasias and dysplasias), or hyperproliferativedisorders of the skin, lung, liver, bone, brain, stomach, colon, breast,prostate, bladder, kidney, pancreas, ovary, and/or uterus are treated inaccordance with the methods described herein. In other specificembodiments, a sarcoma, or melanoma is treated as described herein.

In a specific embodiment, the cancer mediated by Bmi-1 being treated asdescribed herein is leukemia, lymphoma or myeloma (e.g., multiplemyeloma). Non-limiting examples of leukemias and other blood-bornecancers mediated by Bmi-1 that can be treated with the methods describedherein include acute lymphoblastic leukemia (ALL), acute lymphoblasticB-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblasticleukemia (AML), acute promyelocytic leukemia (APL), acute monoblasticleukemia, acute erythroleukemic leukemia, acute megakaryoblasticleukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia,acute undifferentiated leukemia, chronic myelocytic leukemia (CML),chronic lymphocytic leukemia (CLL) and hairy cell leukemia.

Non-limiting examples of lymphomas mediated by Bmi-1 that can be treatedin accordance with the methods described herein include Hodgkin'slymphoma, non-Hodgkin's lymphoma, multiple myeloma, Waldenström'smacroglobulinemia, heavy chain disease, and polycythemia vera.

In another embodiment, the cancer mediated by Bmi-1 being treated asdescribed herein is a solid tumor. Examples of solid tumors that can betreated in accordance with the methods described herein include, but arenot limited to fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma,lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma,Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer,colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breastcancer, ovarian cancer, prostate cancer, esophageal cancer, stomachcancer, oral cancer, nasal cancer, throat cancer, squamous cellcarcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervicalcancer, uterine cancer, testicular cancer, small cell lung carcinoma,bladder carcinoma, lung cancer, epithelial carcinoma, glioma,glioblastoma multiforme, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, skin cancer, melanoma,neuroblastoma, and retinoblastoma.

In certain embodiments, a cancer mediated by Bmi-1 includes, but is notlimited to, brain cancer, gastric cancer, hematologic cancer, lungcancer, non-small cell lung cancer, pancreatic cancer, prostate cancer,salivary gland cancer, colorectal carcinoma, hepatocellular carcinoma,liver carcinoma, breast carcinomas or sarcomas, esophageal carcinomas orsarcomas, stomach carcinomas or sarcomas, fibrosarcoma, glioblastoma,diffuse intrinsic pontine glioma, medulloblastoma, neuroblastoma,diffuse large B cell lymphomas, B cell non-Hodgkin's lymphoma, Hodgkin'slymphoma or chronic or acute myeloid leukemia.

In certain embodiments, a cancer mediated by Bmi-1 includes, but is notlimited to, tumors that relapse after therapy despite improved surgicaland irradiation techniques. Tumor relapse may occur for a number ofreasons, with one plausible explanation being the existence of cancerstem cells (CSC) or tumor stem cells (tumor initiating cells) in thetumor population. CSCs are defined as a population of stem cellsrelative to any type of blood cancer, solid tumor cancer or metastaticcancer. Tumor stem cells are those specifically found within a tumor.Both have characteristics similar to normal stem cells. Like normal stemcells, CSCs and tumor stem cells have the potential to self-renew.Unlike normal stem cells, though, due to the sustained presence of highlevels of Bmi-1, the CSCs and tumor stem cells fail to terminallydifferentiate and proliferate unchecked. Their enhanced DNA repaircapacity also enables them to become resistant to cytotoxic,chemotherapeutic drugs designed to kill cancer cells and tumor cells.Therefore, targeting CSCs and tumor stem cells that overexpress Bmi-1could be an approach for effective cancer treatment. One furtherapproach is to target various transcription factors responsible formaintenance of the self renewal capacity of CSCs and tumor stem cells.

As used herein, the term “treat,” “treatment” or “treating” refers to:(i) preventing a disease, disorder and/or condition from occurring in asubject that may be predisposed to the disease, disorder and/orcondition but has not yet been diagnosed as having said disease,disorder and/or condition; (ii) inhibiting a disease, disorder and/orcondition, i.e., arresting its development; and/or (iii) relieving adisease, disorder and/or condition, i.e., causing regression of thedisease, disorder and/or condition.

As used herein, the term “subject” refers to members of the human,equine, porcine, bovine, murine, rattus, canine and feline species. Insome embodiments, the subject is a mammal or a warm-blooded vertebrateanimal. In other embodiments, the subject is a human. As used herein,the term “patient” may be used interchangeably with “subject” and“human”.

In certain embodiments, the subject is a human that is 0 to 6 monthsold, 6 to 12 months old, 6 to 18 months old, 18 to 36 months old, 1 to 5years old, 5 to 10 years old, 10 to 15 years old, 15 to 20 years old, 20to 25 years old, 25 to 30 years old, 30 to 35 years old, 35 to 40 yearsold, 40 to 45 years old, 45 to 50 years old, 50 to 55 years old, 55 to60 years old, 60 to 65 years old, 65 to 70 years old, 70 to 75 yearsold, 75 to 80 years old, 80 to 85 years old, 85 to 90 years old, 90 to95 years old or 95 to 100 years old. In some embodiments, the subject isa human infant. In other embodiments, the subject is a human toddler. Inother embodiments, the subject is a human child. In other embodiments,the subject is human adult. In yet other embodiments, the subject is anelderly human.

As used herein, the term “elderly human” refers to a human 65 years orolder; the term “human adult” refers to a human that is 18 years orolder; the term “human child” refers to a human that is 1 year to 18years old; the term “human infant” refers to a newborn to 1 year oldyear human; and, the term “human toddler” refers to a human that is 1year to 3 years old.

In certain embodiments, the subject is in an immunocompromised state orimmunosuppressed state or at risk for becoming immunocompromised orimmunosuppressed. In certain embodiments, the subject is receiving orrecovering from an immunosuppressive therapy. In certain embodiments,the subject has or is at risk of getting cancer, AIDS, or a bacterialinfection. In certain embodiments, the subject is, will or has undergonesurgery, chemotherapy and/or radiation therapy. In certain embodiments,the subject has cystic fibrosis, pulmonary fibrosis or another conditionaffecting the lungs. In certain embodiments, the subject has, will haveor had a tissue transplant.

In some embodiments, the subject's cancer, due to the overexpression ofBmi-1 in cancer cells, tumor cells, cancer stem cells or tumor stemcells thereof, has proven refractory to conventional “standard of care”therapies (excluding treatment with a compound of Formula (I) or a formthereof), such that the patient has discontinued the conventionaltherapy. In one embodiment, without being limited by theory, the term“refractory” means that at least some significant portion of the cancercells, tumor cells, cancer stem cells or tumor stem cells continue toproliferate due to the overexpression of Bmi-1, despite therapy. Thedetermination of whether the cancer is refractory to a particulartherapy can be made either in vivo or in vitro by any method known inthe art for assaying the effect of a therapy on the cancer cells, tumorcells, cancer stem cells or tumor stem cells, using the art-acceptedmeanings of “refractory” in such a context. In certain embodiments, apatient having a refractory cancer due to the overexpression of Bmi-1 isa patient in which the cancer is non-responsive or resistant to aconventional or “standard of care” therapy. In certain embodiments, apatient with refractory cancer has a cancer mediated by Bmi-1 thatprogresses. Disease progression, as a lack of clinical response to atherapy, is demonstrated when the tumor or neoplasm has not beensignificantly eradicated and/or the symptoms have not been significantlyalleviated. The determination of whether a patient has a refractorycancer mediated by Bmi-1 can be made either in vivo or in vitro by anymethod known in the art for assaying the effectiveness of the therapyfor the treatment of the cancer, using art-accepted meanings of“refractory” in such a context.

In certain embodiments, the patient to be treated in accordance with themethods described herein is a patient already being treated withantibiotics, anti-virals, anti-fungals, or other biological therapy,immunotherapy or anti-cancer therapy. Among these patients are patientswith a refractory cancer mediated by Bmi-1 or patients too young forconventional therapies. In some embodiments, the patient being treatedis treatment naive, not having received any prior therapy. In any of theforegoing embodiments, a patient to be treated may receive a smallmolecule therapy.

In some embodiments, a compound of Formula (I) or a form thereof may beprophylactically administered to a patient to prevent the onset ofcancer mediated by Bmi-1 in a patient at risk of developing cancer. Insome embodiments, a compound of Formula (I) or a form thereof may betherapeutically administered to a patient that is susceptible to adversereactions to conventional therapies. In some embodiments, the subjectbeing administered one or more compounds of Formula (I) or a formthereof has not received prior therapy. In other embodiments, one ormore compounds of Formula (I) or a form thereof are administered to asubject who has received a prior therapy. In some embodiments, thesubject administered a compound of Formula (I) or a form thereof hasdiscontinued a prior therapy due to lack of benefit from the therapy,adverse effects from the therapy or unacceptable levels of toxicity.

In some embodiments, the subject being administered one or morecompounds of Formula (I) or a form thereof, will or has undergonesurgery, chemotherapy, antibody therapy, hormonal therapy and/orradiation therapy. In certain embodiments, the patient has undergonesurgery to remove the tumor or neoplasm. In certain embodiments, thesubject will have, or has had, or is undergoing a tissue or organtransplant.

As used herein, the terms “effective amount,” “prophylacticallyeffective amount” or “therapeutically effective amount” mean an amountof a compound of Formula (I) or a form thereof that is effective ininhibiting Bmi-1 protein function and reducing the level of Bmi-1protein, as described herein, and thus producing the desiredprophylactic, therapeutic, ameliorative, inhibitory or preventativeeffect in a cancer mediated by Bmi-1 in a patient in need thereof.

As used herein, the term “effective amount,” in the context ofadministering a compound of Formula (I) or a form thereof to a patient,refers to the amount of a compound of Formula (I) or a form thereofwhich is sufficient to achieve at least one or more of the followingeffects, as applicable, in a patient or in patient cell(s): (i)inhibition of Bmi-1 protein function; (ii) reduction in the level orquantity of Bmi-1 protein; (iii) reduction or amelioration in theseverity of a cancer mediated by Bmi-1 or a symptom associatedtherewith; (iv) prevention of the progression of a cancer mediated byBmi-1 or a symptom associated therewith; (v) regression of a cancermediated by Bmi-1 or a symptom associated therewith; (vi) prevention ofthe development or onset of a cancer mediated by Bmi-1 or a symptomassociated therewith; (vii) prevention of the recurrence of a cancermediated by Bmi-1 or a symptom associated with a cancer mediated byBmi-1; (viii) reduction of the duration of a symptom associated with acancer mediated by Bmi-1; (ix) reduction or elimination of the cancerstem cell or tumor stem cell population; (x) reduction or elimination ofthe growth of a tumor or neoplasm overexpressing Bmi-1; (xi) reductionor elimination of the proliferation of cancer cells or tumor cells;(xii) reduction or elimination of the formation of a tumor or neoplasmoverexpressing Bmi-1; (xiii) eradication or control of a primary,regional and/or metastatic cancer mediated by Bmi-1; (xiv) reduction inpatient mortality; (xv) increased number of patients in remission; (xvi)increased length of remission in patients; (xvii) the size of a tumor orneoplasm overexpressing Bmi-1 is maintained or controlled such that thesize does not increase or increases less than the size of the tumorafter administration of a standard therapy as measured by conventionalmethods available to one of skill in the art, such as MRI, X-ray and CATscan; (xviii) increased delay in disease progression; (xix) increasedpatient survival; (xx) reduction in incidences of patienthospitalization; (xxi) reduction in the length of patienthospitalization; (xxii) enhancement or improvement in the prophylacticor therapeutic effect(s) of another therapy; (xxiii) reduction in thenumber of symptoms associated with a cancer mediated by Bmi-1; (xxiv)increased cancer-free survival of patients; and/or (xxv) increasedsymptom-free survival of cancer patients.

In general, the term “effective amount” also includes that amount of acompound of Formula (I) or a form thereof administered to a patientwhich is in a range of from about 0.001 mg/Kg/day to about 500mg/Kg/day, or about 0.01 mg/Kg/day to about 500 mg/Kg/day, or about 0.1mg to about 500 mg/Kg/day, or about 1.0 mg/day to about 500 mg/Kg/day,in single, divided, or a continuous dose for a patient or subject havinga weight in a range of between about 40 to about 200 Kg (which dose maybe adjusted for patients or subjects above or below this range,particularly children under 40 Kg). The typical adult subject isexpected to have a median weight in a range of between about 60 to about100 Kg. The effective amount for the subject will also depend uponvarious factors, including the body weight, size and health of thesubject. An effective amount for a given patient can be determinedaccording to the skill and judgment of the clinician.

In another embodiment, where daily doses are adjusted based upon theweight of the subject or patient, compounds of Formula (I) or a formthereof described herein may be formulated for delivery at about 0.02,0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30,0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0,5.0, 10, 20 or 50 mg/Kg/day. Daily doses adjusted based upon the weightof the subject or patient may be administered as a single, divided, orcontinuous dose. In embodiments where a dose of a compound of Formula(I) or a form thereof is given more than once per day, the dose may beadministered once, twice, three times, or more per day. In anotherembodiment, a subject is administered one or more doses of an effectiveamount of a compound of Formula (I) or a form thereof, wherein theeffective amount may not be the same for each dose.

Another embodiment described herein includes an effective amount of thecompound of Formula (I) or a form thereof in a range of from about 0.001mg/Kg/day to about 500 mg/Kg/day.

Within the scope described herein, the “effective amount” of a compoundof Formula (I) or a form thereof for use in the manufacture of amedicament or in a method for treating a cancer mediated by Bmi-1 in asubject in need thereof, is intended to include an amount in a range offrom about 0.1 ng to about 3500 mg administered daily; from about 0.1 μgto about 3500 mg administered daily; from about 0.1 mg to about 3500 mgadministered daily; from about 1 mg to about 3500 mg administered daily;from about 1 mg to about 3000 mg administered daily; from about 0.05 mgto about 1500 mg administered daily; from about 0.5 mg to about 1500 mgadministered daily; from about 1 mg to about 1500 mg administered daily;from about 5 mg to about 1500 mg administered daily; from about 10 mg toabout 600 mg administered daily; from about 0.5 mg to about 2000 mgadministered daily; or, an amount in a range of from about 5.0 mg toabout 1500 mg administered daily.

Another embodiment described herein includes an effective amount of thecompound of Formula (I) or a form thereof in a range of from about 0.1ng to about 3500 mg.

For any compound of Formula (I) or a form thereof, the effective amountcan be estimated initially by results from cell culture assays or fromrelevant animal models, such as the mouse, chimpanzee, marmoset ortamarin animal model. Relevant animal models may also be used todetermine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic efficacy andtoxicity may be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., ED₅₀ (the dose therapeuticallyeffective in 50% of the population) and LD₅₀ (the dose lethal to 50% ofthe population). The dose ratio between the toxic and therapeutic effectis referred to as the therapeutic index, and can be expressed as theratio, LD₅₀/ED₅₀. In some embodiments, the effective amount is such thata large therapeutic index is achieved. In further embodiments, thedosage is within a range of plasma concentrations that include an ED₅₀with little or no toxicity. The dosage may vary within this rangedepending upon the dosage form employed, sensitivity of the patient, andthe route of administration.

More specifically, the concentration-biological effect (pharmacodynamic)relationship observed with regard to a compound of Formula (I) or a formthereof suggests a target plasma concentration ranging from about 0.001μg/mL to about 50 μg/mL, from about 0.01 μg/mL to about 20 μg/mL, fromabout 0.05 μg/mL to about 10 μg/mL, or from about 0.1 μg/mL to about 5μg/mL. To achieve such plasma concentrations, the compounds of Formula(I) or a form thereof described herein may be administered at doses thatvary from 0.001 μg to 100,000 mg, depending upon the route ofadministration in single, divided, or continuous doses for a patientweighing between about 40 to about 100 kg (which dose may be adjustedfor patients above or below this weight range, particularly for childrenunder 40 kg).

The exact dosage will be determined by the practitioner, in light offactors related to the subject. Dosage and administration may beadjusted to provide sufficient levels of the active agent(s) or tomaintain the desired effect. Administration factors that may be takeninto account include the severity of the disease state, general healthof the subject, ethnicity, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, tolerance for toxicity related to drug metabolites,experience with other cancer therapies and regimens, andtolerance/response to such therapies and regimens. Long-actingpharmaceutical compositions may be administered every 2, 3 or 4 days,once every week, or once every two weeks depending on half-life andclearance rate of the particular formulation.

The compounds of Formula (I) or a form thereof described herein may beadministered to the subject via any drug delivery route known in theart. Nonlimiting examples include oral, ocular, rectal, buccal, topical,nasal, ophthalmic, subcutaneous, intramuscular, intravenous (bolus andinfusion), intracerebral, transdermal, and pulmonary routes ofadministration.

Compound Metabolites

Also falling within the scope described herein are the in vivo metabolicproducts of the compounds of Formula (I) or a form thereof. Suchproducts may result, for example, from the oxidation, reduction,hydrolysis, amidation, glucuronidation, esterification and the like ofthe administered compound of Formula (I) or a form thereof, primarilydue to enzymatic processes. Accordingly, the compounds of Formula (I) ora form thereof described herein include those produced by a processcomprising contacting a compound of Formula (I) or a form thereofdescribed herein with a mammalian tissue or a mammal for a period oftime sufficient to yield a metabolic product thereof.

Such products typically are identified by preparing a radio-labeled(e.g. C¹⁴ or H³) compound of Formula (I) or a form thereof describedherein, administering it in a detectable dose (e.g., greater than about0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, or toman, allowing sufficient time for metabolism to occur (typically about30 seconds to 30 hours), and isolating its conversion products fromurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites may be done inthe same way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of Formula (I) or a form thereof describedherein even if they possess no biological activity of their own.

Combination Therapies

The methods of treating a cancer mediated by Bmi-1 in a subject in needthereof, in addition to those previously described herein, furthercomprise administering to the subject in need thereof an effectiveamount of one or more of the compounds of Formula (I) or a form thereofalone or in combination with one or more additional agents selected fromanti-cancer agents, anti-proliferative agents, chemotherapeutic agents,immunomodulatory agents, anti-angiogenic agents, anti-inflammatoryagents, alkylating agents, steroidal and non-steriodal anti-inflammatoryagents, pain relievers, leukotriene antagonists, β2-agonists,anticholinergic agents, hormonal agents, biological agents, tubulinbinding agents, glucocorticoids, corticosteroid agents, antibacterialagents, antihistamines, anti-malarial agents, anti-viral agents,antibiotics and the like; and, optionally with radiation therapy.

In another embodiment, one or more compounds of Formula (I) or a formthereof alone or in combination with one or more additional agents maybe administered to the subject in combination with a supportive therapy,a pain relief therapy, or other therapy that does not have an effect ona cancer mediated by Bmi-1.

In some embodiments, one or more compounds of Formula (I) or a formthereof described herein and one or more additional agents describedherein are administered as the same pharmaceutical composition. Incertain embodiments, one or more compounds of Formula (I) or a formthereof described herein and one or more additional agents describedherein are administered in different pharmaceutical compositions. Incertain embodiments, one or more compounds of Formula (I) or a formthereof described herein and one or more additional agents describedherein are administered by the same route of administration. In certainembodiments, one or more compounds of Formula (I) or a form thereofdescribed herein and one or more additional agents described herein areadministered by different routes of administration.

In other embodiments are pharmaceutical compositions wherein one or morecompounds of Formula (I) or a form thereof are administered in acombination product with one or more additional agents useful in thetreatment of a cancer mediated by Bmi-1. The skilled artisan willrecognize that a variety of active ingredients may be administered in acombination with the compounds of Formula (I) or a form thereofdescribed herein whereby the product may act to augment orsynergistically enhance the anticancer activity of either or both theadditional agent(s) and the compound(s) of Formula (I) or a form thereofdescribed herein.

As used herein, the term “synergistic,” refers to the effect of theadministration of a combination product as described herein which ismore effective than the additive effects of any two or more singleagents. In a specific embodiment, a synergistic effect of a combinationproduct permits the use of lower dosages of one or more agents and/orless frequent administration of said agents to a subject with a cancermediated by Bmi-1. In certain embodiments, the ability to utilize lowerdosages of an agent and/or to administer said agents less frequentlyreduces the toxicity associated with the administration of said agentsto a subject without reducing the efficacy of said agents in theprevention or treatment of a cancer mediated by Bmi-1. In someembodiments, a synergistic effect results in improved efficacy of eachof the agents in treating a cancer mediated by Bmi-1. In someembodiments, a synergistic effect of a combination of agents avoids orreduces adverse or unwanted side effects associated with the use of anysingle agent. The combination of agents in such a product can beadministered to a subject in the same pharmaceutical composition.Alternatively, the agents can be administered concurrently to a subjectin separate pharmaceutical compositions. The agents may also beadministered to a subject by the same or different routes ofadministration. In a specific embodiment, at least one of the agents isa compound of Formula (I) or a form thereof described herein.

It is also possible to combine any compound of Formula (I) or a formthereof described herein with such additional agents useful in thetreatment of a cancer mediated by Bmi-1, including compounds of Formula(I) or a form thereof as described herein, in a unitary dosage form, orin separate dosage forms intended for simultaneous or sequentialadministration to a patient in need of treatment. When administeredsequentially, the combination may be administered in two or moreadministrations. In an alternative embodiment, it is possible toadminister one or more compounds of Formula (I) or a form thereofdescribed herein and one or more additional agents described herein bydifferent routes.

According to the methods described herein, a combination product mayinclude a combination of active ingredients that may be: (1)co-formulated and administered or delivered simultaneously in a combinedformulation; (2) delivered sequentially or in parallel as separateformulations; or (3) by any other combination regimen known in the art.When delivered as separate formulations in alternation therapy, themethods described herein may comprise administration or delivery, forexample, without limitation, in separate solutions, emulsions,suspensions, tablets, pills or capsules, or by different injections inseparate syringes. In general, when administered in alternation, aneffective dosage of each active ingredient is administered serially, onedose following another. In contrast, in parallel or simultaneousadministration, effective dosages of two or more active ingredients areadministered together. Various alternative combinations of intermittentsequential or in parallel combination administration may also be used.

Specific examples of such agents include, but are not limited to,immunomodulatory agents (e.g., interferon, penicillamine and the like),anti-angiogenic agent, anti-inflammatory agents (e.g., adrenocorticoids,corticosteroids (e.g., beclomethasone, budesonide, flunisolide,fluticasone, triamcinolone, methylprednisolone, prednisolone,prednisone, hydrocortisone), glucocorticoids, steroidal andnon-steriodal anti-inflammatory drugs (e.g., aspirin, ibuprofen,diclofenac, and COX-2 inhibitors)), pain relievers, leukotrieneantagonists (e.g., montelukast, methyl xanthines, zafirlukast, andzileuton), β2-agonists (e.g., albuterol, biterol, fenoterol, isoetharie,metaproterenol, pirbuterol, salbutamol, terbutalin formoterol,salmeterol, and salbutamol terbutaline), anticholinergic agents (e.g.,ipratropium bromide and oxitropium bromide), antibacterial agents (e.g.,sulphasalazine, dapsone and the like), antihistamines, anti-malarialagents (e.g., hydroxychloroquine), anti-viral agents (e.g., nucleosideanalogs (e.g., zidovudine, acyclovir, gangcyclovir, vidarabine,idoxuridine, trifluridine, ribavirin, foscarnet, amantadine,rimantadine, saquinavir, indinavir, ritonavir, and AZT) and antibiotics(e.g., dactinomycin (formerly actinomycin), bleomycin, erythomycin,penicillin, mithramycin, and anthramycin (AMC)).

Specific examples of additional agents that may be used in combinationwith a compound of Formula (I) or a form thereof described hereininclude, but are not limited to: acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthracyclin; anthramycin; asparaginase; asperlin;azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide;bisantrene hydrochloride; bisnafide dimesylate; bisphosphonates (e.g.,pamidronate (Aredria®), sodium clondronate (Bonefos®), zoledronic acid(Zometa®), alendronate (Fosamax®), etidronate, ibandornate, cimadronate,risedromate, and tiludromate); bizelesin; bleomycin sulfate; brequinarsodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide;carbetimer; carboplatin; carmustine; carubicin hydrochloride;carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine;demethylation agents; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; EphA2 inhibitors; elsamitrucin;enloplatin; enpromate; epipropidine; epirubicin hydrochloride;erbulozole; esorubicin hydrochloride; estramustine; estramustinephosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;fludarabine phosphate; 5-fluorouracil; fluorocitabine; fosquidone;fostriecin sodium; gemcitabine; gemcitabine hydrochloride; histonedeacetylase inhibitors; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; imatinib mesylate; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alpha-2a; interferonalpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; lenalidomide; letrozole; leuprolide acetate; liarozolehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride;masoprocol; maytansine; mechlorethamine hydrochloride; anti-CD2antibodies; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; volitinib; vorozole;zeniplatin; zinostatin; zorubicin hydrochloride and the like.

Other examples of treating a cancer mediated by Bmi-1 include treatmentwith an anti-cancer or anti-proliferative agent wherein the anti-canceror anti-proliferative agent is selected from, but not limited to:20-Epi-1,25-dihydroxyvitamin D3 (MC 1288, MC 1301, KH 1060);5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA(0-palmitoyl-1-thioglycerol); arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole(CaRest M3); CARN 700; cartilage derived inhibitor; carzelesin; caseinkinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;cladribine; clomifene analogues; clotrimazole; collismycin A;collismycin B; combretastatin A4; combretastatin analogue; conagenin;crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives;curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabineocfosfate (YNK01 or Starasid®); cytolytic factor; cytostatin;dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, dioxamycin;diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; HMG CoAreductase inhibitors (e.g., atorvastatin, cerivastatin, fluvastatin,lescol, lupitor, lovastatin, rosuvastatin, and simvastatin); hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide/estrogen/progesterone combinations; leuprorelin; levamisole;LFA-3TIP (see, International Publication No. WO93/0686 and U.S. Pat. No.6,162,432); liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline;lytic peptides; maitansine; mannostatin A; marimastat; masoprocol;maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;menogaril; merbarone; meterelin; methioninase; metoclopramide; MIFtautomerase inhibitor; mifepristone; miltefosine; mirimostim; mismatcheddouble stranded RNA; mitoguazone; mitolactol; mitomycin analogues;mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone;mofarotene; molgramostim; monoclonal antibody, human chorionicgonadotrophin; monophosphoryl lipid A/myobacterium cell wall skeleton(CWS/MPL); mopidamol; multiple drug resistance gene inhibitor; multipletumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxideB; mycobacterial cell wall extract; myriaporone; N-acetyldinaline;N-substituted benzamides; nafarelin; nagrestip; naloxone/pentazocinecombinations; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine (BCX-34); pentosanpolysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide;perillyl alcohol dehydrogenase; phenazinomycin; phenylacetate;phosphatase inhibitors; picibanil; pilocarpine hydrochloride;pirarubicin; piritrexim; placetin A; placetin B; plasminogen activatorinhibitor; platinum complex; platinum compounds; platinum-triaminecomplex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;prostaglandin J2; proteasome inhibitors; protein A-based immunemodulator; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RH retinamide; rogletimide; rohitukine; romurtide;roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescencederived inhibitor 1; sense oligonucleotides; signal transductioninhibitors; signal transduction modulators; single chain antigen bindingprotein; sizofiran; sobuzoxane; sodium borocaptate; sodiumphenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactiveintestinal peptide antagonist; suradista; suramin; swainsonine;synthetic glycosaminoglycans; tallimustine; 5-fluorouracil; leucovorin;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;thalidomide; velaresol; veramine; verdins; verteporfin; vinorelbine;vinxaltine; volitinib; vorozole; zanoterone; zeniplatin; zilascorb;zinostatin stimalamer and the like.

In some embodiments, the additional agent that may be used incombination with a compound of Formula (I) or a form thereof describedherein is one or more immunomodulatory agent(s). Non-limiting examplesof immunomodulatory agents include proteinaceous agents such ascytokines, peptide mimetics, and antibodies (e.g., human, humanized,chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)₂ fragments orepitope binding fragments), nucleic acid molecules (e.g., antisensenucleic acid molecules and triple helices), cancer molecules, organiccompounds, and inorganic compounds.

In particular, one or more immunomodulatory agents that may be used incombination with a compound of Formula (I) or a form thereof describedherein include, but are not limited to, methotrexate, leflunomide,cyclophosphamide, cytoxan, cyclosporine A, minocycline, azathioprine(Imuran®), antibiotics (e.g., FK506 (tacrolimus)), methylprednisolone(MP), corticosteroids, steroids, mycophenolate mofetil, rapamycin(sirolimus), mizoribine, deoxyspergualin, brequinar,malononitriloamindes (e.g., leflunamide), T-cell receptor modulators,cytokine receptor modulators, and modulators mast cell modulators.

In one embodiment, the immunomodulatory agent is a chemotherapeuticagent. In an alternative embodiment, the immunomodulatory agent is animmunomodulatory agent other than a chemotherapeutic agent. In someembodiments, the additional agent used described herein is not animmunomodulatory agent.

In some embodiments, the additional agent that may be used incombination with a compound of Formula (I) or a form thereof describedherein is one or more anti-angiogenic agent(s). Non-limiting examples ofanti-angiogenic agents include proteins, polypeptides, peptides, fusionproteins, antibodies (e.g., human, humanized, chimeric, monoclonal,polyclonal, Fvs, ScFvs, Fab fragments, F(ab)₂ fragments, andantigen-binding fragments thereof) such as antibodies thatimmunospecifically bind to TNF-α, nucleic acid molecules (e.g.,antisense molecules or triple helices), organic molecules, inorganicmolecules, and cancer molecules that reduce or inhibit angiogenesis. Inother embodiments, the additional agent described herein is not ananti-angiogenic agent.

In some embodiments, the additional agent that may be used incombination with a compound of Formula (I) or a form thereof describedherein is one or more anti-inflammatory agent(s). Non-limiting examplesof anti-inflammatory agents include any anti-inflammatory agent usefulin treating inflammatory disorders. Non-limiting examples ofanti-inflammatory agents include non-steroidal anti-inflammatory drugs(NSAIDs), steroidal anti-inflammatory drugs, anticholinergics (e.g.,atropine sulfate, atropine methylnitrate, and ipratropium bromide(ATROVENT®), β2-agonists (e.g., albuterol (VENTOLIN® and PROVENTIL®),bitolterol (TORNALATE®), levalbuterol (XOPONEX®), metaproterenol(ALUPENT®), pirbuterol (MAXAIR®), terbutlaine (BRETHAIRE® andBRETHINE®), albuterol (PROVENTIL®, REPETABS®, and VOLMAX®), formoterol(FORADIL AEROLIZER®), salmeterol (SEREVENT® and SEREVENT DISKUS®)),methylxanthines (e.g., theophylline (UNIPHYL®, THEO-DUR®, SLO-BID®, ANDTEHO-42®)) and the like. Examples of NSAIDs include, but are not limitedto, aspirin, ibuprofen, celecoxib (CELEBREX®), diclofenac (VOLTAREN®),etodolac (LODINE®), fenoprofen (NALFON®), indomethacin (INDOCIN®),ketoralac (TORADOL®), oxaprozin (DAYPRO®), nabumentone (RELAFEN®),sulindac (CLINORIL®), tolmentin (TOLECTIN®), rofecoxib (VIOXX®),naproxen (ALEVE®, NAPROSYN®), ketoprofen (ACTRON®), nabumetone(RELAFEN®) and the like. Such NSAIDs function by inhibiting acyclooxgenase enzyme (e.g., COX-1 and/or COX-2). Examples of steroidalanti-inflammatory drugs include, but are not limited to,glucocorticoids, dexamethasone (DECADRON®), corticosteroids (e.g.,methylprednisolone (MEDROL®)), cortisone, hydrocortisone, prednisone(PREDNISONE® and DELTASONE®), prednisolone (PRELONE® and PEDIAPRED®),triamcinolone, azulfidine, inhibitors of eicosanoids (e.g.,prostaglandins, thromboxanes or leukotrienes) and the like.

In certain embodiments, the additional agent that may be used incombination with a compound of Formula (I) or a form thereof describedherein is an alkylating agent, a nitrosourea, an antimetabolite, ananthracyclin, a topoisomerase II inhibitor, a mitotic inhibitor and thelike. Alkylating agents include, but are not limited to, busulfan,cisplatin, carboplatin, cholormbucil, cyclophosphamide, ifosfamide,decarbazine, mechlorethamine, mephalen, temozolomide and the like.Nitrosoureas include, but are not limited to, carmustine (BiCNU®),lomustine (CeeNU®) and the like. Antimetabolites include, but are notlimited to, 5-fluorouracil, capecitabine, methotrexate, gemcitabine,cytarabine, fludarabine and the like. Anthracyclins include, but are notlimited to, daunorubicin, doxorubicin, epirubicin, idarubicin,mitoxantrone and the like. Topoisomerase II inhibitors include, but arenot limited to, topotecan, irinotecan, etopiside (VP-16), teniposide andthe like. Mitotic inhibitors include, but are not limited to, taxanes(paclitaxel, docetaxel), the vinca alkaloids (vinblastine, vincristine,and vinorelbine) and the like.

In more specific embodiments, the additional anti-cancer agent,anti-proliferative agent or chemotherapeutic agent that may be used incombination with a compound of Formula (I) or a form thereof describedherein includes, and is not limited to aflibercept, amsacrine,bleomycin, busulfan, capecitabine, carboplatin, carmustine,chlorambucil, cisplatin, cladribine, clofarabine, crisantaspase,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin(IV and liposomal), docetaxel, doxorubicin (IV and liposomal),enzastaurin, epirubicin, etoposide, fludarabine, 5-fluorouracil (5-FU),gemcitabine, gliadel implants, hydroxycarbamide, idarubicin, ifosfamide,imatinib mesylate, irinotecan, lanreotide, lenalidomide, leucovorin,lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin,mitoxantrone, octreotide, oxaliplatin, paclitaxel, pemetrexed,pentostatin, procarbazine, raltitrexed, satraplatin, sorafenib,streptozocin, sunitinib, tegafur-uracil, temozolomide, teniposide,thalidomide, thiotepa, tioguanine, topotecan, treosulfan, vatalanib,vinblastine, vincristine, vindesine, vinorelbine, volitinib, ZD6474,monoclonal antibodies (such as bevacizumab, cetuximab, IMC-A12,IMC-1121B, medi-522, rituximab and the like), hormonal agents (such asanastrozole, bicalutamide, buserelin, cyproterone, diethylstilbestrol,exemestane, flutamide, goserelin (breast and prostrate), letrozole,leuprorelin, medroxyprogesterone, megestrol acetate, tamoxifen,toremifene, triptorelin and the like), biological agents (such asinterferon, interleukin-12 and the like), angiogenesis receptor tyrosinekinase (RTK) inhibitors (such as AE-941, angiostatin,carboxyamidotriazole, cilengitide, endostatin, halofuginonehydrobromide, 2-methoxyestradiol, squalamine lactate, SU6668 and thelike), tubulin binding agents (such as combretastatin A4 phosphate andthe like), matrix metalloproteinase inhibitors (such as BMS-275291 andthe like) and/or serine/threonine/tyrosine kinase inhibitors and anoptional nonsteroidal or COX-2 anti-inflammatory agent (such ascelecoxib and the like) or corticosteroid agents (such as prednisone andthe like).

In more particular embodiments, one or more additional anti-cancer,anti-proliferative or chemotherapeutic agents that may be used incombination with a compound of Formula (I) or a form thereof describedherein is selected from bevacizumab, carboplatin, cisplatin, docetaxel,doxorubicin, exemestane, gemcitabine, 5-fluorouracil, imatinib,irinotecan, sorafenib, sunitinib, temozolomide, volitinib orcombinations thereof.

In some embodiments, a compound of Formula (I) or a form thereofdescribed herein and one or more additional anti-cancer,anti-proliferative or chemotherapeutic agents is used in combinationwith radiation therapy comprising the use of x-rays, gamma rays andother sources of radiation to destroy cancer cells or tumor cells. Inspecific embodiments, the radiation therapy is administered as externalbeam radiation or teletherapy, wherein the radiation is directed from aremote source. In other embodiments, the radiation therapy isadministered as internal therapy or brachytherapy wherein a radioactivesource is placed close to cancer cells, tumor cells and/or a tumor mass.

Currently available anti-cancer, anti-proliferative or chemotherapeuticagents, their dosage regimens, routes of administration and recommendedusage alone or in combination are known in the art and have beendescribed in literature such as the Physician's Desk Reference.

Any anti-cancer, anti-proliferative or chemotherapeutic agent oranti-cancer therapy which is known to be useful, or which has been usedor is currently being used for the treatment of a cancer mediated byBmi-1, can be used in combination with compounds of Formula (I) or aform thereof described herein. See, e.g., Gilman et al., Goodman andGilman's: The Pharmacological Basis of Therapeutics, 10th ed.,McGraw-Hill, New York, 2001; The Merck Manual of Diagnosis and Therapy,Berkow, M. D. et al. (eds.), 17th Ed., Merck Sharp & Dohme ResearchLaboratories, Rahway, N J, 1999; Cecil Textbook of Medicine, 20th Ed.,Bennett and Plum (eds.), W.B. Saunders, Philadelphia, 1996, andPhysician's Desk Reference for information regarding cancer therapies(e.g., using prophylactic or therapeutic agents) which have been or arecurrently being used for preventing, treating and/or managing a cancermediated by Bmi-1.

Pharmaceutical Compositions

The present description is also directed to a pharmaceutical compositionfor use in treating a cancer mediated by Bmi-1 comprising an effectiveamount of a compound of Formula (I) or a form thereof in admixture witha pharmaceutically acceptable excipient.

An embodiment described herein includes a pharmaceutical compositionmade by the process of admixing a compound of Formula (I) or a formthereof with a pharmaceutically acceptable excipient. The pharmaceuticalcomposition may also be formulated to achieve a physiologicallycompatible pH of about pH 7, ranging from about pH 3 to about pH 11.

Another embodiment includes the use of a compound of Formula (I) or aform thereof in a pharmaceutical composition for use in treating acancer mediated by Bmi-1 comprising an effective amount of a compound ofFormula (I) or a form thereof in admixture with a pharmaceuticallyacceptable excipient.

As used herein, the term “composition” means a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in the specified amounts.

In another embodiment, the pharmaceutical composition for use intreating a cancer mediated by Bmi-1 may comprise a combination productof one or more compounds of Formula (I) or a form thereof describedherein and one or more additional agents useful in the treatment of acancer mediated by Bmi-1, such as an anti-cancer, anti-proliferative,chemotherapeutic or biochemotherapeutic agent.

The term “pharmaceutically acceptable excipient” refers to apharmacologically inactive substance formulated for administration withan active pharmaceutical agent, such as the compounds of Formula (I) ora form thereof described herein. The term refers to any pharmaceuticalexcipient that may be administered without undue toxicity.Pharmaceutically acceptable excipients may be determined in part by theparticular composition being administered, as well as by the particularmode of administration and/or dosage form. Nonlimiting examples ofpharmaceutically acceptable excipients include carriers, solvents,stabilizers, adjuvants, diluents, etc. Accordingly, there exists a widevariety of suitable formulations of pharmaceutical compositions asdescribed herein (see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowlymetabolized macromolecules such as proteins, polysaccharides, polylacticacids, polyglycolic acids, polymeric amino acids, amino acid copolymers,and inactive virus particles. Other exemplary excipients includeantioxidants such as ascorbic acid; chelating agents such as EDTA;carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water,saline, glycerol and ethanol; wetting or emulsifying agents; pHbuffering substances; and the like. Liposomes are also included withinthe definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated inany form suitable for the intended method of administration. Suitableformulations for oral administration include solids, liquid solutions,emulsions and suspensions, while suitable inhaleable formulations forpulmonary administration include liquids and powders. Alternativeformulations include syrups, creams, ointments, tablets, and lyophilizedsolids which can be reconstituted with a physiologically compatiblesolvent prior to administration.

When intended for oral use for example, tablets, troches, lozenges,aqueous or oil suspensions, non-aqueous solutions, dispersible powdersor granules (including micronized particles or nanoparticles),emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation.

Pharmaceutically acceptable excipients suitable for use in conjunctionwith tablets include, for example, inert fillers, such as celluloses,calcium or sodium carbonate, lactose, calcium or sodium phosphate;disintegrating agents, such as croscarmellose sodium, cross-linkedpovidone, maize starch, or alginic acid; binding agents, such aspovidone, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample celluloses, lactose, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with non-aqueousor oil medium, such as glycerin, propylene glycol, polyethylene glycol,peanut oil, liquid paraffin or olive oil.

In other embodiments, pharmaceutical compositions described herein foruse in treating a cancer mediated by Bmi-1 may be formulated assuspensions comprising a compound of Formula (I) or a form thereofdescribed herein in admixture with at least one pharmaceuticallyacceptable excipient suitable for the manufacture of a suspension. Inyet other embodiments, pharmaceutical compositions described herein maybe formulated as dispersible powders and granules suitable forpreparation of a suspension by the addition of one or more excipient(s).

Excipients suitable for use in connection with suspensions includesuspending agents, such as sodium carboxymethylcellulose,methylcellulose, hydroxypropyl methylcelluose, sodium alginate,polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wettingagents such as a naturally occurring phosphatide (e.g., lecithin), acondensation product of an alkylene oxide with a fatty acid (e.g.,polyoxyethylene stearate), a condensation product of ethylene oxide witha long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), acondensation product of ethylene oxide with a partial ester derived froma fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitanmonooleate); and thickening agents, such as carbomer, beeswax, hardparaffin or cetyl alcohol. The suspensions may also contain one or morepreservatives such as acetic acid, methyl and/or n-propylp-hydroxy-benzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions described herein may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth;naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids; hexitol anhydrides, such assorbitan monooleate; and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions described herein may be inthe form of a sterile injectable preparation, such as a sterileinjectable aqueous emulsion or oleaginous suspension. Such emulsion orsuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,2-propane-diol.The sterile injectable preparation may also be prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution, isotonic sodium chloride solution and thelike. In addition, sterile fixed oils may be employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or di-glycerides. In addition, fatty acidssuch as oleic acid may likewise be used in the preparation ofinjectables.

The compounds of Formula (I) or a form thereof described herein may besubstantially modified by substitutions or additions of chemical orbiochemical moieties which make them more suitable for delivery (e.g.,increase solubility, bioactivity, palatability, decrease adversereactions, etc.), for example by esterification, glycosylation,PEGylation and the like.

In some embodiments, the compound of Formula (I) or a form thereofdescribed herein is formulated for oral administration in formulationsthat enhance the oral bioavailability of such compounds of Formula (I)or a form thereof. As such, pharmaceutical compositions described hereinmay comprise a effective amount of a compound of Formula (I) or a formthereof, together with at least one pharmaceutically acceptableexcipient selected from medium chain fatty acids or propylene glycolesters thereof (e.g., propylene glycol esters of edible fatty acids suchas caprylic and capric fatty acids) and pharmaceutically acceptablesurfactants, such as polyoxyl 40 hydrogenated castor oil and the like.

In other embodiments, the bioavailability of a compound of Formula (I)or a form thereof may be enhanced by using particle size optimizationtechniques including, but not limited to, the preparation ofnanoparticles or nanosuspensions using techniques known to those skilledin art. The compound forms present in such preparations includeamorphous, partially amorphous, partially crystalline or crystallineforms.

In alternative embodiments, the pharmaceutical composition may furthercomprise one or more aqueous solubility enhancer(s), such as acyclodextrin. Nonlimiting examples of cyclodextrin includehydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosylderivatives of α-, β-, and γ-cyclodextrin, andhydroxypropyl-β-cyclodextrin (HPBC). In some embodiments, thepharmaceutical composition further comprises HPBC in a range of fromabout 0.1% to about 20%, from about 1% to about 15%, or from about 2.5%to about 10%. The amount of solubility enhancer employed may depend onthe amount of the active pharmaceutical ingredient in the composition.

General Synthetic Examples

As disclosed herein, the methods for preparing the compounds of Formula(I) or a form thereof described herein commonly use standard, well-knownsynthetic methodology. Many of the starting materials are commerciallyavailable or can be prepared in the Specific Synthetic Examples thatfollow using techniques known to those skilled in the art. Functionaltransformations to modify substituents may also be undertaken wherechemically feasible and are considered to be included within the scopeof the General Schemes and the knowledge of a person of ordinary skillin the art. Compounds of Formula (I) or a form thereof can be preparedas described in the Schemes below.

Compound A2 is prepared by reacting an amine substituted pyrimidineCompound A1 (wherein X₁ represents a halogen atom selected from bromo,chloro or iodo) with a protecting group (wherein PG represents aprotecting group such as di-tert-butyldicarbonate and the like) in thepresence of a catalyst (such as 4-dimethylaminopyridine and the like) ina solvent (such as dichloromethane and the like) at a suitabletemperature.

Compound A2 is coupled with various substituted aryl, heteroaryl orheterocyclyl amines or amides (wherein PG represents an optionallypresent protecting group monosubstituted on the amine) in the presenceof a strong base (such as KOtBu, NaOtBu, NaO^(t)Am, NaH, NaHMDS and thelike) in a solvent (such as THF, DMF and the like), followed bydeprotection using techniques known to those of skill in the art toprovide a Compound A3.

Alternatively, Compound A3 may be prepared by reacting Compound A2 withvarious substituted aryl, heteroaryl or heterocyclyl amines (wherein theprotecting group is absent) via a palladium catalyzed cross-couplingreaction using a mixture of a phosphino ligand:palladium source (whereinthe palladium source is selected from Pd₂(dba)₃, PdCl₂(allyl),PdCl₂(ACN), [Pd(OAc)₂]₃ and the like and the phosphino ligand isselected from PCy₃, Q-Phos, XPhos and the like; alternatively, thepalladium:ligand complex may be selected from Pd(dppf)Cl₂, Pd(PPh₃)₄ andthe like). Each isomer may be isolated from the mixture using separationtechniques known to those of ordinary skill in the art, followed bydeprotection also using techniques known to those of skill in the art.

Using either route, an intermediate product is obtained as a mixture ofregioisomers, wherein the term “Sep” refers to isolating the desiredCompound A3 isomer to be carried forward from the mixture usingseparation techniques known to those of ordinary skill in the art.

Compound A5 is prepared by cross-coupling Compound A3 with a nitrosubstituted aryl or heteroaryl amine Compound A4 (wherein Ar representsan aromatic or heteroaromatic ring; and, wherein Ra represents one, twoor three optional R₅ substituents) via a palladium catalyzedcross-coupling reaction using a mixture of a phosphino ligand:palladiumsource (wherein the palladium source is selected from Pd₂(dba)₃,PdCl₂(allyl), PdCl₂(ACN), [Pd(OAc)₂]₃ and the like and the phosphinoligand is selected from PCy₃, Q-Phos, XPhos and the like; alternatively,the palladium:ligand complex may be selected from Pd(dppf)Cl₂, Pd(PPh₃)₄and the like).

Compound A6 is prepared by reacting Compound A5 in the presence of ahydrogenation reagent (such as hydrogen gas and the like) in thepresence of a catalyst (such as nickel, platinum on carbon, palladium oncarbon and the like).

Compound A8 is prepared by condensation of Compound A6 with anorthoester Compound A7 (wherein Rb represents an additional optional R₅substituent and Rc represents C₁₋₃alkyl) in the presence of an acid(such as HOAc and the like) or at elevated temperature, followed bydeprotection using techniques known to those of skill in the art.

Compound A8 may also be prepared by cyclizing Compound A6 with a varietyof reactants to obtain the addition of the optional R₅ substituent. Forexample, the reactant may be TCDI, wherein the additional optional R₅substituent is a thio-carbonyl which may be further substituted.

Alternatively, Compound A3 is reacted with a substituted diamineCompound A9 (wherein Ar represents an aromatic or heteroaromatic ring,Ra represents one, two or three optional R₅ substituents and PGrepresents an optional protecting group) via a palladium catalyzedcross-coupling reaction using a mixture of a phosphino ligand:palladiumsource (wherein the palladium source is selected from Pd₂(dba)₃,PdCl₂(allyl), PdCl₂(ACN), [Pd(OAc)₂]₃ and the like and the phosphinoligand is selected from PCy₃, Q-Phos, XPhos and the like; alternatively,the palladium:ligand complex may be selected from Pd(dppf)Cl₂, Pd(PPh₃)₄and the like), followed by deprotection using techniques known to thoseof skill in the art to provide a Compound A6.

Compound A12 is prepared by reacting a Compound A10 (wherein X₂represents a halogen atom selected from bromo, chloro, fluoro or iodo)with Compound A11 (wherein R₁ is a substituted heteroaromatic orheterocyclic monocyclic or bicyclic ring system; and, wherein X₃represents a reactive hydrogen atom attached to a nitrogen atom of R₁).

Compound A14 is prepared by reacting Compound A13 with an aqueousammonia source in a mixture with a solvent (wherein the solvent isselected from CH₃CN, DMSO, mixtures thereof and the like), then couplingCompound A14 with various substituted aryl, heteroaryl or heterocyclylamines (wherein PG represents an optionally present protecting groupmonosubstituted on the amine) in the presence of a strong base (such asKOtBu, NaOtBu, NaO^(t)Am, NaH, NaHMDS and the like) in a solvent in thepresence of a solvent (such as THF, DMF, NMP and the like), followed bydeprotection using techniques known to those of skill in the art toprovide Compound A15.

The intermediate product of the described reactions is obtained as amixture of regioisomers, wherein the term “Sep” refers to isolating thedesired isomer to be carried forward from the mixture using separationtechniques known to those of ordinary skill in the art.

Compound B1 is prepared by coupling Compound A6 with a substituted acylchloride (wherein Rb represents an optional R₆ substituent) at reflux inan organic solvent (such as acetonitrile and the like).

Compound A8 is prepared by reacting B1 in an organic solvent (such asDMA and the like). The reaction may be carried out at elevatedtemperatures.

Compound C2 is prepared by reacting a substituted pyrimidine Compound C1(wherein X₁ represents a halogen atom selected from bromo, chloro oriodo; and Rc represents C₁₋₃alkyl) with a substituted1,2-diaminobenezene Compound A9 (wherein Ar represents an aromatic orheteroaromatic ring, Ra represents one, two or three optional R₅substituents and PG represents an optional protecting group) in thepresence of a base (such as NaH, K₂CO₃ and the like) in a solvent (suchas DMF and the like) at a suitable temperature, followed by deprotectionusing techniques known to those of skill in the art.

Compound C2 is reacted with an orthoester Compound A7 (wherein Rb and Rcare as defined above) in the presence of an acid (such as HOAc and thelike) or at elevated temperature to provide a substituted benzimidazoleCompound C3.

Compound C4 is prepared by reacting Compound C3 with an oxidizing agent(such as mCPBA, MPS, KMnO₄ and the like) in a solvent (such as CH₂Cl₂and the like) at a suitable temperature.

Compound C5 is prepared by reacting Compound C4 with a substituted aryl,heteroaryl or heterocyclyl amine (wherein PG represents an optionallypresent protecting group monosubstituted on the amine) in the presenceof a strong base (such as KOtBu, NaOtBu, NaO^(t)Am, NaH, NaHMDS and thelike) in a solvent (such as THF, DMF, dioxane and the like or mixturesthereof) at a suitable temperature, followed by deprotection usingtechniques known to those of skill in the art.

A substituted pyrimidine Compound D1 (wherein X₁ represents a halogenatom selected from bromo, chloro or iodo; and Rc represents C₁₋₃alkyl)is reacted with the substituted 1,2-diaminobenzene Compound A9 (whereinAr represents an aromatic or heteroaromatic ring, Ra represents one, twoor three optional R₅ substituents and PG represents an optionalprotecting group) in a solvent (such as DMSO and the like) at a suitabletemperature to provide a Compound D2, followed by deprotection usingtechniques known to those of skill in the art, and condensation with theorthoester Compound A7 in the presence of an acid (such as HOAc and thelike) or at elevated temperature to provide Compound C4.

Compound E2 is prepared by reacting either a substituted pyrimidineCompound E1 (wherein X₁ represents a halogen atom selected from bromo,chloro or iodo) or Compound D1 (wherein Rc represents C₁₋₃alkyl) with asubstituted aryl, heteroaryl or heterocyclyl amine (wherein PGrepresents an optionally present protecting group monosubstituted on theamine) in the presence of a base (such as KOtBu, NaOtBu, NaO^(t)Am, NaH,NaHMDS and the like) in a solvent (such as THF, DMF and the like) at asuitable temperature, followed by deprotection using techniques known tothose of skill in the art.

Compound E3 is prepared by reacting Compound E2 with the substituteddiaminobenzene Compound A9 in a solvent (such as HOAc, EtOH and thelike) at a suitable temperature, followed by deprotection usingtechniques known to those of skill in the art.

Compound C5 is prepared by reacting Compound E3 with the orthoesterCompound A7 in the presence of an acid (such as HOAc and the like) or atelevated temperature.

Compound F2 is prepared by reacting Compound E2 with a Compound F1(wherein R₁ is a substituted heteroaromatic or heterocyclic monocyclicor bicyclic ring system and X₄ represents a leaving group such as aboronic acid, boronate ester, trialkyltin, zinc chloride and the likeattached to a carbon atom of R₁), in the presence of a mixture of aphosphino ligand:palladium source (wherein the palladium source isselected from Pd₂(dba)₃, PdCl₂(allyl), PdCl₂(ACN), [Pd(OAc)₂]₃ and thelike and the phosphino ligand is selected from PCy₃, Q-Phos, XPhos andthe like; alternatively, the palladium:ligand complex may be selectedfrom Pd(dppf)Cl₂, Pd(PPh₃)₄ and the like).

A Compound G1 is prepared by reacting a Compound C1 (wherein X₁represents a halogen atom selected from bromo, chloro or iodo and Rcrepresents C₁₋₃alkyl) with a Compound F1 (wherein R₁ is a substitutedheteroaromatic or heterocyclic monocyclic or bicyclic ring system and X₄represents a reactive group such as a boronic acid, boronate ester,trialkyltin, zinc chloride and the like attached to a carbon atom ofR₁), in the presence of a mixture of a phosphino ligand:palladium source(wherein the palladium source is selected from Pd₂(dba)₃, PdCl₂(allyl),PdCl₂(ACN), [Pd(OAc)₂]₃ and the like and the phosphino ligand isselected from PCy₃, Q-Phos, XPhos and the like; alternatively, thepalladium:ligand complex may be selected from Pd(dppf)Cl₂, Pd(PPh₃)₄ andthe like).

When one or both of R₂ and R₃ are optionally halogen, an intermediateproduct is obtained as a mixture of regioisomers, wherein the term “Sep”refers to isolating the desired Compound G1 isomer to be carried forwardfrom the mixture using separation techniques known to those of ordinaryskill in the art.

Compound G2 is prepared by reacting Compound G1 with an oxidizing agent(such as mCPBA, MPS, KMnO₄ and the like) in a solvent (such as CH₂Cl₂and the like). Compound G2 may be carried forward using the procedure ofScheme E to obtain a compound representative of a compound of Formula(I).

Scheme H Oxide Substituted Pyrimidine Compounds

Compound H2 is prepared by reacting Compound H1 with an oxidizing agent(such as mCPBA, MPS and the like), representative of a compound ofFormula (IV).

Compound F2 is prepared by reacting a substituted Compound G2 with aCompound I1 (wherein R₄ represents various substituted aryl, heteroarylor heterocyclyl ring systems; and, wherein X₅ represents a substitutedcarbonyl leaving group, wherein the carbonyl is substituted with ahydrogen or a C₁₋₃alkyl substituent) in the presence of a strong base(such as KOtBu, NaOtBu, NaO^(t)Am, NaH, NaHMDS and the like) in asolvent (such as THF, DMF and the like).

Compound C1 is reacted with a Compound 12 (such as an R₁ substituenthaving an acidic proton group, wherein X₃ represents a reactive hydrogenatom attached to a nitrogen atom of R₁) in the presence of a strong base(such as KOtBu, NaOtBu, NaO^(t)Am, NaH, NaHMDS and the like) to providea Compound G1.

Compound F2 may be alternatively prepared by reacting Compound E2(wherein X₁ represents a halogen atom selected from bromo, chloro oriodo) with a Compound I3 (wherein R₁ represents a substitutedheteroaromatic or heterocyclic monocyclic or bicyclic ring system and X₆represents a reactive hydrogen atom attached to a carbon atom of R₁) viaa palladium catalyzed cross-coupling reaction using a mixture of aphosphino ligand:palladium source (wherein the palladium source isselected from Pd₂(dba)₃, PdCl₂(allyl), PdCl₂(ACN), [Pd(OAc)₂]₃ and thelike and the phosphino ligand is selected from PCy₃, Q-Phos, XPhos andthe like; alternatively, the palladium:ligand complex may be selectedfrom Pd(dppf)Cl₂, Pd(PPh₃)₄ and the like) and a base (such as cesiumacetate and the like) in an organic solvent (such as DMA and the like).The reaction may be carried out at elevated temperatures.

SPECIFIC SYNTHETIC EXAMPLES

To assist in understanding the scope of the compounds of Formula (I) ora form thereof described herein, the following Specific Examples areincluded. The experiments relating to the compounds of Formula (I) or aform thereof described herein should not, of course, be construed asspecifically limiting the scope of the compounds of Formula (I) or aform thereof described herein and such variations of the compounds ofFormula (I) or a form thereof as described herein, now known or laterdeveloped, which would be within the purview of one skilled in the artare considered to fall within the scope as described herein andhereinafter claimed.

Other than in the working examples, unless indicated to the contrary,all numbers expressing quantities of ingredients, reaction conditions,experimental data, and so forth used in the specification and claims areto be understood as being modified by the term “about”. Accordingly, allsuch numbers represent approximations that may vary depending upon thedesired properties sought to be obtained by a reaction or as a result ofvariable experimental conditions. Therefore, within an expected range ofexperimental reproducibility, the term “about” in the context of theresulting data, refers to a range for data provided that may varyaccording to a standard deviation from the mean. As well, forexperimental results provided, the resulting data may be rounded up ordown to present data consistently, without loss of significant figures.At the very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should be construed in light of the number of significantdigits and ordinary rounding techniques.

While the numerical ranges and parameters setting forth thecharacterization of the compounds of Formula (I) or a form thereofdescribed herein are approximations, the numerical values set forth inthe working examples are reported as precisely as possible. Anynumerical value, however, inherently contains certain errors necessarilyresulting from the standard deviation found in their respective testingmeasurements.

The compounds of Formula (I) or a form thereof provided herein aredescribed in more detail with reference to the following non-limitingexamples, which are offered to more fully illustrate the scope of thecompounds of Formula (I) or a form thereof described herein, but are notto be construed as limiting the scope thereof. The examples illustratethe preparation of compounds of Formula (I) or a form thereof describedherein, and the testing of these compounds of Formula (I) or a formthereof in vitro and/or in vivo. Those of skill in the art willunderstand that the synthesis techniques described in these examplesrepresent techniques that fall within the practice of those havingordinary skill in the chemical arts, and as such constitute preferredmodes for the practice thereof. However, it should be appreciated thatthose having skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificmethods that are disclosed herein while still obtaining a like orsimilar result without departing from the spirit and scope describedherein.

The reagents and solvents were used as purchased (from a variety ofvendors), except where noted. Where applicable, the term “Celite” isused as shown in the following examples to represent the tradenameCELITE® (brand of diatomaceous earth). Where applicable, chromatographicseparations were performed using techniques and equipment commonlyavailable such as, for example, by using an ISCO CombiFlash® Rf system.Where applicable, NMR spectra were obtained using techniques andequipment commonly available such as, for example, by using a BrukerAvance III⁵⁰⁰ spectrometer with deuterated solvents such as, forexample, DMSO-d₆ or residual solvent as standard. Where applicable,melting points were determined using techniques and equipment commonlyavailable such as, for example, by using a SRS OptiMelt® MPA100 (valuesas obtained without correction/calibration). Where applicable, TLCanalysis was performed using techniques and equipment commonly availablesuch as, for example, by using Aldrich 254 nm glass-backed plates (60 Å,250 μm), visualized using UV and I₂ stains. Where applicable, ESI massspectra were obtained using techniques and equipment commonly availablesuch as, for example, by using an ACQUITY UPLC® System, with valuesshown as [M+H]⁺ or [M−H]⁻, unless otherwise indicated. Where applicable,the structure of the product was obtained via a 2D NOESY (NuclearOverhausEr SpectroscopY) experiment.

The following abbreviations are provided to ensure the terms used hereinare unambiguous to one skilled in the art:

Abbreviation Meaning AcOH or HOAc acetic acid ACN or MeCN acetonitrileAlMe₃ trimethylaluminum APC allylpalladium (II) chloride dimer Boctert-butoxycarbonyl CsOAc cesium acetate DCM or CH₂Cl₂ dichloromethaneDME dimethyl ether DMF dimethyl formamide DMA dimethylacetamide DMAP4-dimethylaminopyridine DMSO dimethylsulfoxide EtOAc ethyl acetate EtOHethanol HPLC high performance liquid chromatography h, hr, min, s hour(h or hr), minute (min), second (s) iPrMgCl*LiCl isopropylmagnesiumchloride lithium chloride complex iPrOAc isopropyl acetate K₂CO₃potassium carbonate K₃PO₄ potassium phosphate KOtBu or potassiumtert-butoxide t-BuOK LC/MS, LCMS or liquid chromatographic massspectroscopy LC-MS MeOH methanol MeNH₂ × HCl methanamine hydrochlorideMS mass spectroscopy m.p. melting point (shown in ° Centigrade) MPSpotassium peroxymonosulfate or OXONE ® NaH sodium hydride NaHCO₃ sodiumbicarbonate NaHMDS sodium hexamethyldisilazide NaIO₄ sodium periodateNaOH sodium hydroxide NaOtAm sodium tent-pentoxide NaOMe sodiummethoxide NaOEt sodium ethoxide NaOtBu sodium tert-butoxide NCSN-chlorosuccinimide NH₄Cl ammonium chloride NH₄OH ammonium hydroxide NISN-iodosuccinimide NMP N-methylpyrrolidone NMR nuclear magnetic resonancePCl₅ phosphorus perchloride or phosphorus pentachloride PCy₃tricyclohexylphosphine [Pd] palladium Pd/C^(o) palladium on carbonPd₂(dba)₃ or tris(dibenzylideneacetone)dipalladium(0) Pd₂dba₃Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)PdCl₂(ACN) bis(acetonitrile)dichloropalladium(II) PdCl₂(allyl)chloroallylpalladium(II) dimer [Pd(OAc)₂]₃ palladium (II) acetatePd(PPh₃)₄ tetrakis(triphenylphosphine)palladium POCl₃ phosphorusoxychloride PPh₃ triphenylphosphine psi pounds per square inch pressurePt/C platinum on carbon PTSA p-toluenesulfonic acid Q-Phos or QPhos1,2,3,4,5-pentaphenyl-1′-(di-tert- butylphosphino)ferrocene RT roomtemperature TBSO or OTBS tert-butyldimethylsilyloxy TCDI1,1′-thiocarbonyldiimidazole t-Bu tert-butyl TEA, NEt₃, Et₃Ntriethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydrideTHF tetrahydrofuran TsOH × H₂O p-toluenesulfonic acid monohydrate UPLCultra performance liquid chromatography Xphos or XPhos2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Example 14-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine(Cpd 6)6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 7)

Step 1. To a mixture of 2-methylsulfonyl-4,6-dichloropyrimidine (18 g,75 mmol) dissolved in DMSO (200 mL) was added 1,2-diaminobenzene (24.75g, 225 mmol, 3 Eq.). The reaction was stirred at room temperatureovernight, until LC-MS showed consumption of the starting material. Thereaction mixture was poured into ice-water and extracted with EtOAc. Theester layer was washed with water multiple times, then brine and theresidue was dried to give a brown powder containing a residual amount ofthe 1,2-diaminobenzene starting material (23.1 g)

Step 2. The brown powder (11.5 g, 37.5 mmol) was dissolved in HOAc (50mL), then triethylorthoacetate (8 mL, 50 mmol) was added slowly. Themixture was stirred at room temperature overnight until the reaction wascomplete, as shown by LC-MS. The reaction mixture was filtered and thesolid was washed with 50% EtOAc/hexane, then 100% hexane to give a pureproduct as an off-white powder (11.23 g, 93% for 2 steps).

Step 3. A solution of the off-white powder (6.44 g, 20 mmol) in DMF (30mL) was cooled to −78° C., and 4-trifluoromethylaniline (2.5 mL, 20mmol) was added, followed by a NaO^(t)Am solution (1.4 N in THF, 30 mL).The reaction mixture was gradually warmed to room temperature thenquenched with water and extracted with EtOAc. The ester layer was washedwith water three times, then with brine and concentrated to give a crudeproduct. The product was washed with a small amount of EtOAc to yieldCompound 6 as off-white crystals (6.68 g, 83%); ¹H NMR (500 MHz, CDCl₃)δ 7.77 (3H, d, J=8.6 Hz), 7.61 (3H, d, J=8.6 Hz), 7.35-7.29 (2H, m),7.00 (1H, s), 2.77 (3H, s); MS m/z 404.3 [M+H]⁺.

Step 4. In a pressure tube, Compound 6 (3 g, 7.4 mmol) was dissolved inDMSO (30 mL) and NH₃.H₂O (10 mL) was slowly added. The tube was cappedand heated to 50° C. for 1 day, until LC-MS showed completion of thereaction. The reaction mixture was poured into ice/water and thenextracted with EtOAc. The ester layer was washed with water, then brineand concentrated to give Compound 7 (2.85 g, 100%) as a white powder; ¹HNMR (500 MHz, Acetone-d₆) δ 8.90 (1H, br s), 8.09 (2H, d, J=8.6 Hz),7.62 (2H, m), 7.58 (2H, d, J=8.6 Hz), 7.24 (2H, m), 6.67 (2H, br s),6.35 (1H, s), 2.70 (3H, s); MS m/z 386.3 [M+H]⁺.

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 1 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name & Data 84-chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amine ¹H NMR (500 MHz, CDCl₃) δ 7.83-7.75(3H, m), 7.61 (1H, d, J = 7.2 Hz), 7.57 (1H, t, J = 8.3 Hz), 7.36-7.31(3H, m), 7.06 (1H, s), 2.79 (3H, s); MS m/z 422.3 [M + H]⁺ 13N²-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ9.16 (1H, br s), 8.27 (1H, dd, J = 14.4, 1.2 Hz), 7.65-7.61 (3H, m),7.56 (1H, t, J = 8.5 z), 7.26- 7.23 (2H, m), 6.83 (2H, br s), 6.40 (1H,s), 2.71 (3H, s); MS m/z 403.3 [M + H]⁺ 14N²-14-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.76 (1H, br s), 8.15 (1H, dd, J = 13.9, 2.4 Hz), 7.63 (2H, m), 7.50(1H, m), 7.26-7.21 (4H, m), 6.68 (2H, br s), 6.90 (1H, t, J = 74 Hz),6.33 (1H, s), 2.70 (3H, s); MS m/z 401.3 [M + H]⁺ 152-{[6-(2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol ¹H NMR (500MHz, Acetone-d₆) δ 8.93 (1H, br s), 8.09 (2H, d, J = 8.6 Hz), 7.61 (4H,m), 7.22 (2H, m), 6.38 (1H, s), 3.82 (2H, m), 3.69 (2H, br), 2.70 (3H,s); MS m/z 429.4 [M + H]⁺ 162-{[2-{[3-fluoro-4-(trifluoromethyl)phenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol ¹H NMR (500 MHz,Acetone-d₆) δ 9.16 (1H, br), 8.18 (1H, br), 7.69-7.57 (4H, m), 7.23 (2H,m), 7.13 (1H, br), 6.42 (1H, s), 3.83 (2H, m), 3.69 (2H, br), 2.70 (3H,s); MS m/z 447.4 [M + H]⁺ 172-{[2-{[4-(difluoromethoxy)-3-fluorophenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol ¹H NMR (500 MHz,Acetone-d₆) δ 8.83 (1H, br), 8.08 (1H, br d, J = 12.9 Hz), 7.61 (2H, m),7.55 (1H, br d, J = 7.8 Hz), 7.23 (3H, m), 6.90 (1H, t, J = 74 Hz), 6.35(1H, s), 3.82 (2H, m), 3.67 (2H, br), 2.69 (3H, s); MS m/z 445.4 [M +H]⁺ 18 4-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine ¹H NMR (500 MHz, Acetone-d₆) δ9.73 (1H, br s), 8.05 (2H, d, J = 8.6 Hz), 7.86 (1H, dd, J = 10.9, 7.4Hz), 7.72 (2H, d, J = 8.6 Hz), 7.56 91H, dd, J = 7.5, 5.7 Hz), 7.34 (1H,s), 2.80 (3H, s); MS m/z 440.3 [M + H]⁺ 194-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-2-amine ¹H NMR (500 MHz,Acetone-d₆) δ 9.92 (1H, br s), 8.03 (1H, d, J = 14 Hz), 7.86 (1H, dd, J= 10.7, 7.4 Hz), 7.71 (2H, m), 7.55 (1H, dd, J = 10.7, 7.4 Hz), 7.39(1H, s), 2.80 (3H, s); MS m/z 458.3 [M + H]⁺ 206-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine MS m/z 421.0 [M + H]⁺ 212-{[6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol ¹H NMR (500MHz, Acetone-d₆) δ 8.98 (1H, br s), 8.07 (2H, d, J = 8.5 Hz), 7.66 (1H,dd, J = 10.8, 7.4 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.50 (1H, dd, J = 10.8,7.5 Hz), 3.82 (2H, m), 3.69 (2H, br m), 2.70 (3H, s); MS m/z 465.4 [M +H]⁺ 22 N⁴-hydroxy-6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetonitrile-d₃) δ 8.48 (1H, br. s.) 8.22 (1H, s) 7.93 (2H, d, J = 8.83Hz) 7.64-7.73 (2H, m) 7.60 (2H, d, J = 8.51 Hz) 7.26-7.34 (2H, m) 6.56(1H, s) 2.74 (3H, s); MS m/z 401.1 [M + H]⁺ 236-(2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆)δ 9.72 (1H, s) 8.01 (2H, d, J = 8.51 Hz) 7.63-7.70 (1H, m) 7.53-7.60(3H, m) 7.22-7.30 (2H, m) 7.17 (2 H, br. s.) 6.19 (1H, s) 3.07 (2H, q, J= 7.36 Hz) 1.32 (3H, t, J = 7.41 Hz); MS m/z 399.2 [M + H]⁺ 246-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 9.14 (1H, br s), 8.25 (1H, d, J = 14.6 Hz), 7.69 (1H, dd,J = 10.8, 7.4 Hz), 7.63-7.56 (2H, m), 7.52 (1H, dd, J = 10.8, 7.4 Hz),6.82 (2H, br s), 6.39 (1H, s), 2.70 (3H, s); MS m/z 438.4 [M + H]⁺ 28[3-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)imidazo[1,2-a]pyridin-2-yl]methanol ¹H NMR (500 MHz, Methanol-d₄) δ4.95 (s, 2H) 5.89 (s, 1H) 6.96 (td, J = 6.90, 0.90 Hz, 1H) 7.40-7.47 (m,1H) 7.55-7.66 (m, 6H) 10.06 (d, J = 6.94 Hz, 1H); MS m/z 401.1 [M + H]⁺29 [3-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl]methanol ¹H NMR (500 MHz,Methanol-d₄) δ 5.14 (s, 2H) 5.89 (s, 1H) 7.52- 7.60 (m, 2H) 7.61-7.68(m, 3H) 7.74 (br. s., 1H) 7.77-7.85 (m, 1H) 10.34 (d, J = 2.84 Hz, 1H);MS m/z 419.1 [M + H]⁺ 304-chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amine ¹H NMR (500 MHz, Acetone-d₆) δ 9.57(1H, br s), 7.96 (1H, dd, J = 13.1, 2.6 Hz0, 7.78 (1H, m), 7.65 (1H, m),7.58 (1H, m), 7.35 (1H, t, J = 8.9 Hz), 7.30 (2H, m), 7.28 (1H, s), 6.96(1H, t, J = 73.6 Hz), 2.77 (3H, s); MS m/z 420.3 [M + H]⁺ 316-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆)δ 2.75 (s, 3H) 6.17-6.27 (m, 1H) 7.10-7.28 (m, 2H) 7.53-7.63 (m, 2H)7.94-8.04 (m, 2H) 8.16-8.24 (m, 1H) 8.38-8.50 (m, 1H) 9.75 (br. s, 1H);MS m/z 420.1 [M + H]⁺ 326-(6-chloro-2-ethyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆)δ 1.28-1.38 (m, 3H) 3.06-3.15 (m, 2H) 6.18-6.23 (m, 1H) 7.13-7.29 (m,2H) 7.52-7.62 (m, 2H) 7.94- 8.02 (m, 2H) 8.11-8.18 (m, 1H) 8.41-8.48 (m,1H) 9.72-9.78 (m, 1H); MS m/z 434.1 [M + H]⁺ 364-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine ¹H NMR (500 MHz,Acetone-d₆) δ 9.89 (1H, br s), 9.08 (1H, d, J = 2.4 Hz), 8.62 (1H, dd, dJ = 8.7, 2.2 Hz), 7.86 (1H, d, J = 8.7 Hz), 7.79 (1H, m), 7.65 (1H, m),7.37 (1H, s), 7.30 (2H, m), 2.78 (3H, s); MS m/z 405.3 [M + H]⁺ 376-(2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine ¹H NMR (500 MHz, CDCl₃) δ 8.81 (1H, d, J =2.3 Hz), 8.40 (1H, dd, J = 8.5, 2.3 Hz), 7.74 (1H, d, J = 7.5 Hz), 7.62(1H, d, J = 8.7 Hz), 7.54 (1H, d, J = 7.5 Hz), 7.32-7.24 (3H, m), 6.16(1H, s), 5.13 (2H, br s), 2.75 (3H, s); MS m/z 386.3 [M + H]⁺ 384-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine ¹H NMR (500 MHz, CDCl₃)δ 9.92 (1H, br s), 9.07 (1, d, J = 2.3 Hz), 8.61 (1H, dd, J = 8.6, 2.3Hz), 7.86 (1H, d, J = 8.7 Hz), 7.63 (2H, m), 7.40 (1H, s), 7.11 (1H, m),2.79 (3H, s); MS m/z 423.3 [M + H]⁺ 396-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 9.13 (1H, d, J = 2.4 Hz), 9.10 (1H, br s), 8.60 (1H, dd, J= 8.5, 2.3 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.65 (1H, dd, J = 8.9, 4.8Hz), 7.33 (1H, dd, J = 9.4, 2.5 Hz), 7.04 (1H, td, J = 9.4, 2.5 Hz),6.79 (2H, br s), 6.39 (1H, s), 2.70 (3H, s); MS m/z 404.3 [M + H]⁺ 406-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 9.14 (1H, s), 9.10 (1H, s), 8.60 (1H, dd, J = 8.4, 1.7Hz), 7.72 (1H, d, J = 8.7 Hz), 7.59 (1H, dd, J = 8.7, 5 Hz), 7.44 (1H,dd, J = 9.5, 2.5 Hz), 7.05 (1H, ddd, J = 9.7, 8.8, 2.5 Hz), 2.69 (3H,s); MS m/z 404.3 [M + H]⁺ 436-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 9.13 (1H, d, J = 2.4 Hz), 9.08 (1H, br s), 8.59 (1H, dd, J= 8.7, 2.4 hz), 7.71 (1H, d, J = 8.7 Hz), 7.60 (1H, dd, J = 8.9, 4.7Hz), 7.36 (1H, dd, J = 9.4, 2.5 Hz), 7.05 (1H, td, J = 9.3, 2.5 Hz),6.80 (1H. br s). 6.38 (1H, s), 3.09 (2H, q, J = 7.4 Hz), 1.35 (3H, t, J= 7.4 Hz); MS m/z 418.4 [M + H]⁺ 446-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 9.14 (1H, d, J = 2.4 Hz), 9.09 (1h, br, s), 7.71 (1H, d <J = 8.7 Hz), 7.62 (1H, dd, J = 8.7, 5, Hz), 7.39 (1H, dd, J = 9.4, 2.5Hz), 7.05 (1H, m), 6.80 (2H, br s), 6.38 (1H, s), 3.09 (2H, t, J = 7.5Hz), 1.35 (3H, t, J = 7.5 Hz); MS m/z 418.4 [M + H]⁺ 616-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.96 (1H, br s), 8.12 (2H, d, J = 8.6 Hz), 7.66 (1H, m),7.57-7.55 (3H, m), 7.20 (2H, m), 6.72 (2H, br), 6.45 (1H, s), 2.50 (1H,m), 1.26 (2H, m), 1.07 (2H, m); MS m/z 411.4 [M + H]⁺ 646-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.95 (1H, br s), 8.10 (2H, d, J = 8.6 Hz), 7.69 (1H, dd, J= 1.9, 7.5 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 10.9, 7.5Hz), 6.71 (2h, br), 6.47 (1h, s), 2.46 (1H, m), 1.25 (2H, m), 1.12 (2H,m); MS m/z 447.4 [M + H]⁺ 656-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.90 (1H, br s), 8.07 (2H, d, J = 8.6 Hz), 8.07 (2H, d, J= 8.6 Hz), 7.61 (1H, dd, J = 10.8, 7.4 Hz), 7.59 (2H, d, J = 8.8 Hz),7.54 (1H, dd, J = 10.8, 7.5 Hz), 6.70 (2H, br), 6.33 (1H, s), 3.09 (2H,q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz); MS m/z 435.4 [M + H]⁺ 666-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.61 (1H, br s), 7.91 (2H, d, J = 9 Hz), 7.67 (1H, dd, J =10.9, 7.4 Hz), 7.43 (1H, dd, J = 10.9, 7.4 Hz), 7.11 (2H, d, J = 9 Hz),6.88 (1H, t, J = 75.2 Hz), 6.58 (2H, br), 6.39 (1H, s), 2.46 (1H, m),1.23 (2H, m), 1.12 (2H, m); MS m/z 445.4 [M + H]⁺ 76N²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.59 (1H, br s), 7.86 (2H, d, J = 9.0 Hz), 7.59 (1H, dd, J = 10.9, 7.5Hz), 7.53 (1H, dd, J = 10.9, 7.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 6.88(1H, t, J = 74.8 Hz), 6.59 (2H, br), 6.26 (1H, s), 3.08 (2H, q, J = 7.5Hz), 1.34 (3H, t, J = 7.5 Hz); MS m/z 433.4 [M + H]⁺ 77N²-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.59 (1H, br s), 7.88 (2H, d, J = 9.1 Hz), 7.65 (1H, dd, J = 10.9, 7.4Hz), 7.50 (1H, dd, J = 10.9, 7.4 Hz), 7.11 (2H, d, J = 9.1 Hz), 6.88(1H, t, J = 74.8 Hz), 6.56 (2H, br), 6.27 (1H, s), 2.68 (3H, s); MS m/z419.3 [M + H]⁺ 83N²-[4-(difluoromethoxy)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.64 (1H, brs), 7.88 (2H, d, J = 9.1 Hz), 7.62 (2H, m), 7.22 (2H, m), 7.09 (2H, d, J= 9.1 Hz), 6.88 (1H, t, J = 74.9 Hz), 6.61 (2H, br), 6.28 (1H, s), 2.69(3H, s); MS m/z 383.3 [M + H]⁺ 84N²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.53 (1H, brs), 7.89 (2H, d, J = 9.0 Hz), 7.63 (2H, m), 7.57 (2H, m), 7.23 (2H, m),7.09 (2H, d, J = 9.0 Hz), 6.88 (1H, t, J = 74.8 Hz), 6.55 (2H, br), 6.26(1H, s), 3.09 (2H, q, = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz); MS m/z 397.4[M + H]⁺ 85 6-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.58 (1H, br s), 7.94 (2H, d, J = 9 Hz), 7.63 (1H, m),7.53 (1H, m), 7.20 (2H, m), 7.10 (2H, d, J = 9 Hz), 6.89 (1H, t, J =74.8 Hz), 6.57 (2H, br), 6.36 (1H, s), 2.49 (1H, m), 1.23 (2H, m), 1.08(2H, m); MS m/z 409.3 [M + H]⁺ 956-(2-ethyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 9.14 (1H, d, J= 2.2 Hz), 9.06 (1 H, br s), 8.61 (8.7, 2.2 Hz), 7.71 (1H, d, J = 8.7Hz), 7.64 (1H, m), 7.59 (1H, m), 7.24 2H, m), 6.77 (2H, br), 6.38 (1H,s), 2.81 (3H, s); MS m/z 400.4 [M + H]⁺ 1006-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.94 (1H, br s), 8.35 1H, dd, J = 2.7, 1.7 Hz), 8.08 (2H,d, J = 8.6 Hz), 7.95 (1H, dd, J = 8.9, 2.7 Hz), 7.60 (2H, d, J = 8.6Hz), 6.70 (2H, br), 6.39 (1H, s), 2.77 (3H, s); MS m/z 404.3 [M + H]⁺101 N²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.64 (1H, br s), 8.34 (1H, dd, J = 2.7, 1.7 Hz), 7.92 (1H,dd, J = 8.9, 2.7 Hz), 7.88 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5Hz), 6.89 (1H, t, J = 74.8 Hz), 6.62 (2H, br), 6.32 (1H, s), 2./76 (3H,s); MS m/z 402.3 [M + H]⁺ 1026-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.88 (1H, br s), 8.09 (2H, d, J = 8.6 Hz), 7.65 (1H, dd, J= 8.9, 4.7 Hz), 7.59 (2H, d, J = 8.6 Hz), 733 (1H, dd, J = 9.5, 2.5 Hz),7.05 (1H, m), 6, .66 (2H, br), 6.34 (1H, s), 2.80 (3H, s); MS m/z 403.3[M + H]⁺ 1086-(6-fluoro-2-methyl-4-oxido-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 10.13 (1H, br s), 8.36 (1H, dd, J = 2.7, 1.8 Hz), 8.10(2H, d, J = 8.6 Hz), 7.93 (1H, dd, J = 8.6, 2.7 Hz), 7.70 (2H, d, J =8.6 Hz), 7.62 (2H, br), 6.83 (1H, s), 2.77 (3H, s); MS m/z 420.3 [M +H]⁺ 123 6-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 2.73 (s, 3H) 6.41 (s, 1H) 6.66 (br. s., 2H) 7.16-7.29 (m,2H) 7.55-7.63 (m, 3H) 7.66-7.72 (m, 1H) 8.15 (d, J = 8.51 Hz, 2H) 8.85(s, 1H); MS m/z 417.3 [M + H]⁺ 1276-(2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine MS m/z 331 [M + H]⁺ 129N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (1H, s), 7.67(2H, d, J = 9.0 Hz), 7.66-7.59 (2H, m), 7.30-7.26 (2H, m), 6.97 (2H,br), 6.86 (2H, d, J = 9.0 Hz), 6.10 (1H, s), 3.74 (3H, s), 2.69 (3H, s);m.p. 149-150° C.; MS m/z 347.1 [M + H]⁺ 130N²-(1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (1H, s),7.67-7.56 (3H, m), 7.30-7.25 (2H, m), 7.13 (1H, dd, J = 8.5, 2.1 Hz),7.03 (2H, br), 6.83 (1H, d, J = 8.4 Hz), 6.11 (1H, s), 5.98 (2H, s),2.69 (3H, s); m.p. 118-119° C.; MS m/z 361.1 [M + H]⁺ 131N²-(4-bromophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.66 (1H, br s), 7.84 (2H, d,J = 9 Hz), 7.62 (2H, m), 7.39 (2H, d, J = 9 Hz), 7.22 (2H, m), 6.61 (2H,br), 6.29 (1H, s), 2.69 (3H, s); MS m/z 397.2 [M + H]⁺ 1326-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 9.20 (1H, br s), 8.17 (4H,m), 7.63 (2H, m), 7.25 (2H, m), 6.74 (2H, br), 6.41 (1H, s), 2.71 (3H,s); MS m/z 362.3 [M + H]⁺ 144N²-[4-(dimethylamino)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.12 (1H, brs), 7.62-7.58 (4H, m), 7.23-7.19 (2H, m), 6.71 (2H, br d, J = 8.4 Hz),6.31 (2H, br), 6.17 (1H, s), 2.91 (6H, s), 2.68 (3H, s); MS m/z 360.4[M + H]⁺ 145 4-{[4-amino-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile ¹H NMR (500 MHz, Acetone-d₆) δ 9.04 (1H, br s),8.11 (2H, d, J = 8.9 Hz), 7.65-7.61 (4H, m), 7.24 (2H, m), 6.74 (2H,br), 6.37 (1H, s), 2.69 (3H, s); MS m/z 342.3 [M + H]⁺ 1466-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.71 (1H, br s), 7.97 (2H, d, J = 9.2 Hz), 7.62 (2H, m),7.25-7.21 (4H, m), 6.61 (2H, br), 6.30 (1H, s), 2.69 (3H, s); MS m/z401.3 [M + H]⁺ 147N²-(2,2-difluoro-1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.74 (1H, br s), 8.19 (1H, S), 7.62 (2h, M), 7.40 (1H, dd, J = 9, 2.3Hz), 7.23 (2H, m), 7.15 (1H, d, J = 8.5 Hz), 6.67 (2H, br), 6.29 (1H,s), 2.68 (3H, s); MS m/z 397.3 [M + H]⁺ 148N²-(3-fluoro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (1H, s), 7.87(1H, br d, J = 14.2 Hz), 7.67-7.60 (2H, m), 7.42 (1H, ddd, J = 8.9, 2.5,1.2 Hz), 7.31-7.25 (2H, m), 7.09 (1H, d, J = 18.8 Hz), 7.08 (2H, br s),6.14 (1H, s), 3.82 (3H, s), 2.70 (3H, s); m.p. 186-187° C.; MS m/z 365.2[M + H]⁺ 149N²-(3-chloro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (1H, s), 7.95(1H, d, J = 2.3 Hz), 7.66-7.61 (3H, m), 7.30-7.26 (2H, m), 7.07 (1H, d,J = 9.0 Hz), 7.05 (2H, br), 6.15 (1H, s), 3.83 (3H, s), 2.70 (3H, s);m.p. 113-114° C.; MS m/z 379.2 [M + H]⁺ 150N²-(4-chlorophenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.46 (1H, s), 7.85 (2H, d, J =8.9 Hz), 7.71-7.67 (1H, m), 7.59-7.55 (1H, m), 7.30 (2H, d, J = 8.9 Hz),7.29-7.26 (2H, m), 7.12 (2H, br s), 6.16 (1H, s), 3.08 (2H, q, J = 7.5Hz), 1.34 (3H, t, J = 7.5 Hz); m.p. 172-173° C.; MS m/z 365.2 [M + H]⁺151 6-(2-ethyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (1H, s), 7.70-7.66 (3H, m),7.59-7.55 (1H, m), 7.30-7.26 (2H, m), 6.99 (2H, br s), 6.86 (2H, d, J =9.0 Hz), 6.09 (1H, s), 3.74 (3H, s), 3.08 (2H, q, J = 7.5 Hz), 1.33 (3H,t, J = 7.5 Hz); m.p. 144-145° C.; MS m/z 361.2 [M + H]⁺ 1526-(2-ethyl-1H-benzimidazol-1-yl)-N²-(2-methylphenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 8.41 (1H, s), 7.67-7.63 (1H, m),7.58-7.54 (1H, m), 7.50 (1H, d, J = 7.5 Hz), 7.28-7.24 (2H, m), 7.22(1H, d, J = 7.5 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.06 (1H, td, J = 7.5,1.0 Hz), 6.92 (2H, br s), 6.07 (1H, s), 3.00 (2H, q, J = 7.5 Hz), 2.27(3H, s), 1.27 (3H, t, J = 7.5 Hz); m.p. 119-120° C.; MS m/z 344.9 [M +H]⁺ 153 6-(2-ethyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (1H, s), 7.71-7.67 (1H, m),7.67 (2H, d, J = 8.5 Hz), 7.59-7.55 (1H, m), 7.30-7.26 (2H, m), 7.07(2H, d, J = 8.5 Hz), 7.02 (2H, br s), 6.11 (1H, s), 3.09 (2H, q, J = 7.5Hz), 2.27 (3H, s), 1.34 (3H, t, J = 7.5 Hz); m.p. 159- 160° C.; MS m/z345.2 [M + H]⁺ 154N²-(1,3-benzodioxol-5-yl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (1H, s),7.70-7.67 (1H, m), 7.60-7.56 (2H, m), 7.30-7.26 (2H, m), 7.13 (1H, dd, J= 8.4, 2.1 Hz), 7.05 (2H, br s), 6.82 (1H, d, J = 8.4 Hz), 6.10 (1H, s),5.98 (2H, s), 3.08 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz); m.p.119-121° C.; MS m/z 375.2 [M + H]⁺ 1556-(2-ethyl-1H-benzimidazol-1-yl)-N²-(3-fluoro-4-methoxyphenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.30(1H, s), 7.87 (1H, d, J = 14.0 Hz), 7.71-7.67 (1H, m), 7.60-7.56 (1H,m), 7.41 (1H, ddd, J = 9.0, 2.5, 1.5 Hz), 7.31-7.27 (2H, m), 7.09 (2H,br s), 7.08 (1H, t, J = 9.5 Hz), 6.12 (1H, s), 3.81 (3H, s), 3.08 (2H,q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz); m.p. 104-106° C.; MS m/z 379.2[M + H]⁺ 156 N²-(3-chloro-4-methoxyphenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (1H, s), 7.94(1H, d, J = 2.6 Hz), 7.72-7.68 (1H, m), 7.64 (1H, dd, J = 8.9, 2.2 Hz),7.61- 7.57 (1H, m), 7.32-7.27 (2H, m), 7.07 (1H, d, J = 9.0 Hz), 7.06(2H, br s), 6.13 (1H, s), 3.83 (3H, s), 3.09 (2H, q, J = 7.5 Hz), 1.35(3H, t, J = 7.5 Hz); m.p. 100-103° C.; MS m/z 395.2 [M + H]⁺ 157N²-(6-methoxypyridin-3-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (1H, s), 8.60(1H, br s), 8.03 (1H, dd, J = 8.9, 2.7 Hz), 7.68-7.61 (2H, m), 7.32-7.28(2H, m), 7.07 (2H, br s), 6.78 (1H, d, J = 8.8 Hz), 6.13 (1H, s), 3.84(3 H, s), 2.68 (3H, s); m.p. 104-106° C.; MS m/z 348.2 [M + H]⁺ 177N²-(4-chlorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.67 (1H, brs), 7.88 (2H, d, J = 9 Hz), 7.62 (2H, m), 7.25 (2H, d, J = 9 Hz), 7.22(2H, m), 6.62 (2H, br), 6.29 (1H, s), 2.69 (3H, s); MS m/z 351.3 [M +H]⁺ 179 N²-(4-chloro-3-fluorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.85 (1H, brs), 8.18 (1H, dd, J = 12.7, 2.5 Hz), 7.64-7.60 (2H, m), 7.51 (1H, m),7.34 (1H, t, J = 8.7 Hz), 7.23 (2H, m), 6.72 (2H, br), 6.33 (1H, s),2.69 (3H, s); MS m/z 369.3 [M + H]⁺ 1806-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 2.67(s, 3H) 3.76 (s, 3H) 6.20 (s, 1H) 6.45 (br. s., 2H) 6.82-6.89 (m, 2H)7.49 (dd, J = 10.72, 7.57 Hz, 1H) 7.64 (dd, J = 11.03, 7.25 Hz, 1H)7.67-7.73 (m, 2H) 8.29 (br. s., 1H); MS m/z 383.3 [M + H]⁺ 1816-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 2.27(s, 3H) 2.68 (s, 3H) 6.23 (s, 1H) 6.49 (br. s., 2H) 7.08 (d, J = 8.20Hz, 2H) 7.50 (dd, J = 10.72, 7.57 Hz, 1H) 7.65 (dd, J = 11.03, 7.25 Hz,1H) 7.68-7.73 (m, 2H) 8.38 (br. s., 1H); MS m/z 366.9 [M + H]⁺ 182N²-(4-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 2.68 (s, 3H)6.28 (s, 1H) 6.60 (br. s., 2H) 7.25-7.30 (m, 2H) 7.50 (dd, J = 10.88,7.41 Hz, 1H) 7.65 (dd, J = 10.72, 7.25 Hz, 1H) 7.86-7.93 (m, 2H) 8.65(br. s, 1 H); MS m/z 387.2 [M + H]⁺ 183N²-(4-methylphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (1H, br s),7.67 (2H, d, J = 8.4 Hz), 7.41 (2H, s), 7.07 (2H, d, J = 8.4 Hz), 6.98(2H, br s), 6.09 (1H, s), 3.37 (3H, s), 2.65 (3H, s), 2.35 (3H, s), 2.34(3H, s); m.p. 111-112° C.; MS m/z 359.1 [M + H]⁺ 184N²-(4-chlorophenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (1H, s), 7.85(2H, d, J = 9.0 Hz), 7.41 (1H, s), 7.40 (1H, s), 7.31 (2H, d, J = 9.0Hz), 7.08 (2H, br s), 6.14 (1H, s), 2.65 (3H, s), 2.35 (3H, s), 2.34(3H, s); m.p. 111-112° C.; MS m/z 379.1 [M + H]⁺ 185N²-(4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.06 (1H, s), 7.66(2H, d, J = 8.9 Hz), 7.40 (2H, s), 6.94 (2H, br s), 6.86 (2H, d, J = 8.9Hz), 6.07 (1H, s), 3.74 (3H, s), 2.64 (3H, s), 2.34 (3H, s), 2.33 (3H,s); m.p. 113-114° C.; MS m/z 375.4 [M + H]⁺ 186N²-(3-fluoro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (1H, s),7.88 (1H, d, J = 3.9 Hz), 7.42 (1H, dd, J = 2.4, 1.3 Hz), 7.41 (2H, s),7.08 (1H, t, J = 9.4 Hz), 7.04 (2H, br s), 6.11 (1H, s), 3.82 (3H, s),2.65 (3H, s), 2.35 (3H, s), 2.33 (3H, s); m.p. 120-121° C.; MS m/z 393.4[M + H]⁺ 187N²-(3-chloro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (1H, s),7.96 (1H, d, J = 2.6 Hz), 7.65 (1H, dd, J = 9.0, 2.4 Hz), 7.41 (2H, s),7.07 (1H, d, J = 9.1 Hz), 7.02 (2H, br s), 6.12 (1H, s), 3.83 (3H, s),2.66 (3H, s), 2.35 (3H, s), 2.34 (3H, s); m.p. 129-131° C.; MS m/z 409.3[M + H]⁺ 188 N²-98 4-(difluoromethoxy)phenyl]-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ9.36 (1H, s), 7.84 (2H, d, J = 9.0 Hz), 7.413 (1H, s), 7.412 (1H, s),7.14 (1H, t, J = 74.6 Hz), 7.10 (2 H, d, J = 9.0 Hz), 7.04 (2H, br s),6.13 (1H, s), 2.66 (3H, s), 2.35 (3 H, s), 2.34 (3H, s); m.p. 89-91° C.;MS m/z 411.1 [M + H]⁺ 191N²-(4-chlorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.63 (1H, brs), 7.87 (2H, d, J = 9 Hz), 7.63 (8.9, 4.8 Hz), 7.32 (1H, dd, J = 9.2,2.5 Hz), 7.26 (2H, 9 Hz), 7.03 (1H, td, J = 9.2, 2.5 Hz), 6.60 (2H, br),6.28 (1H, s), 5.61 (1H, s), 2.69 (3H, s); MS m/z 369.3 [M + H]⁺ 192N²-(4-chloro-3-fluorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.81 (1H, br s), 8.18 (1H, dd, J = 12.7, 2.3 Hz), 7.64 (1H, dd, J = 8.8,4.8 Hz), 7.51 (1H, dd, J = 8.8, 1.5 Hz), 7.38-7.31 (2H, m), 7.04 (1H,td, J = 9.2, 2.5 Hz), 6.71 (2H, br), 6.32 (1H, s), 5.62 (1H, s), 2.69(3H, s); MS m/z 387.3 [M + H]⁺ 193N²-(3-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine MS m/z 387.1 [M + H]⁺ 1946-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine MS m/z 398.2 [M + H]⁺ 1956-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine MS m/z 367.3 [M + H]⁺ 1966-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamine MS m/z 383.3 [M + H]⁺

Example 26-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile(Cpd 68)

A mixture of Compound 18 (44 mg, 0.1 mmol), NaSO₂Me (10 mg, 0.1 mmol)and Bu₄NCN (30 mg, 0.11 mmol) in DMSO (2 mL) was stirred at roomtemperature for 2 hours. Aqueous workup followed by flash chromatographygave the title compound as a white solid (36 mg) in 84% yield. ¹H NMR(500 MHz, Acetone-d₆) δ 9.89 (1H, br s), 8.03 (2H, d, J=8.6 Hz), 7.94(1H, dd, J=10.9, 7.4 Hz), 7.79 (1H, s), 7.73 (2H, d, J=8.6 Hz), 7.56(1H, dd, J=10.6, 7.5 Hz), 2.84 (3H, s); MS m/z 431.4 [M+H]⁺.

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 2 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name & Data 676-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile ¹H NMR (500 MHz,Acetone-d₆) δ 9.92 (1H, br s), 8.07 (2H, d, J = 8.6 Hz), 7.95 (1H, dd, J= 10.7, 7.5 Hz), 7.90 (1H, s), 7.75 (2H, d, J = 8.6 Hz), 7.52 (1H, dd, J= 10.6, 7.5 Hz), 2.54 (1H, m), 1.32 (2 H, m), 1.22 (2H, m); MS m/z 457.4[M + H]⁺

Example 36-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide (Cpd 110)

A mixture of Compound 7 (153 mg, 0.4 mmol), and mCPBA (70% pure, 123 mg,0.5 mmol) was suspended in CH₂Cl₂ (3 mL) and stirred at room temperaturefor 1 day. The reaction mixture was diluted with EtOAc and washedsuccessively with 1N NaOH, then water and brine. The ester layer wasconcentrated under vacuum and the residue was purified using a shortsilica gel column eluted with EtOAc, then 0-10% MeOH/EtOAc, to give thetitle compound as a pale yellow powder (127 mg, 79% yield). ¹H NMR (500MHz, Acetone-d₆) δ 10.21 (1H, br s), 8.12 (2H, d, J=8.6 Hz), 7.68 (2H,d, J=8.6 Hz), 7.63 (3H, m), 7.24 (2H, m), 6.77 (1H, s), 2.70 (3H, s); MSm/z 401.3 [M+H]⁺.

Example 46-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide (Cpd 112)

A mixture of Compound 4 (168 mg, 0.4 mmol) and mCPBA (123 mg, 70% pure,0.5 mmol) was stirred in CH₂Cl₂ (3 mL) at room temperature overnight,then mCPBA (60 mg) was added and the mixture was stirred for 1 day. Thereaction mixture was diluted with EtOAc and washed with 1N NaOH, thenwater and brine. The ester layer was concentrated and purified by columnchromatography to give the title compound as a pale yellow powder (126mg, 75% yield). ¹H NMR (500 MHz, Acetone-d₆) δ 10.22 (1H, br s), 8.10(2H, d, J=8.5 Hz), 7.72 (2H, br), 7.66 (2H, d, J=8.5 Hz), 7.59 (1H, dd,J=8.7, 5 Hz), 7.43 (1H, d, J=7.6 Hz), 7.05 (1H, m), 6.77 (1H, s), 2.68(3H, s); MS m/z 419.4 [M+H]⁺.

Example 56-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide (Cpd 116)

To a solution of Compound 61 (41 mg, 0.1 mmol) in MeOH (2 mL) was addeda solution of MPS (123 mg, 0.2 mmol) in water (1 mL). A whiteprecipitate formed instantly. The suspension was stirred at roomtemperature overnight until LC-MS showed completion of the reaction. Thereaction mixture was diluted with EtOAc, then washed with NaHCO₃ andbrine. The ester layer was dried to give the title compound as anoff-white solid (42 mg, 98% yield). ¹H NMR (500 MHz, Acetone-d₆) δ 10.18(1H, br s), 8.17 (2H, d, J=7.9 Hz), 7.67-7.63 (4H, m), 7.56 (1H, m),7.22 (2H, m), 6.85 (1H, s), 2.46 (1H, m), 1.27 (2H, m), 1.07 (2H, m); MSm/z 427.4 [M+H]⁺

Additional compounds described herein may be prepared according to theprocedure of Example 5 by substituting the appropriate startingmaterials, reagents and reaction conditions:

Cpd Name and Data 115N²-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 3-oxide ¹H NMR (500 MHz,Acetone-d₆) δ 9.93 (1H, br s), 7.87 (2H, d, J = 9 Hz), 7.65 (1H, dd, J =10.7, 7.4 Hz), 7.60 (2H, br), 7.51 (1H, dd, J = 10.7, 7.4 Hz), 7.18 (2H,d, J = 9 Hz), 6.93 (1H, t, J = 74.4 Hz), 6.71 (1H, s), 2.67 (3H, s); MSm/z 435.3 [M + H]⁺ 118 6-(2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide ¹H NMR (500 MHz,Acetone-d₆) δ 10.04 (1H, br s) 7.99 (2H, d, J = 8.51 Hz) 7.45-7.60 (6H,m) 7.11-7.18 (2H, m) 6.64 (1H, s) 2.98 (2H, q, J = 7.46 Hz) 1.24 (3H, t,J = 7.41 Hz); MS m/z 415.3 [M + H]⁺ 1196-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide ¹H NMR (500 MHz,Acetone-d₆) δ 10.3 (1H, br s), 8.10 (2H, d, J = 8.5 Hz), 7.79 (2H, br),7.67 (2H, d, J = 8.5 Hz), 7.63 (1H, dd, J = 8.8, 4.9 Hz), 7.42 (1H, d, J= 9.3, 2.5 Hz), 7.05 (2H, m), 6.78 (1H, s), 3.06 (2H, q, J = 7.5 Hz),1.34 (3H, t, J = 7.5 Hz); MS m/z 433.4 [M + H]⁺ 1996-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide ¹H NMR (500 MHz,Acetone-d₆) δ 10.13 (1H, br s), 8.11 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J= 8.6 Hz), 7.66 (1H, dd, J = 8.9, 4.8 Hz), 7.59 (2H, br), 7.35 (1H, dd,J = 9.4, 7.5 Hz), 7.07 (1H, td, J = 9.3, 7.5 Hz), 6.78 (1H, s), 2.71(3H, s); MS m/z 419.3 [M + H]⁺

Example 65-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine(Cpd 178)

Step 1. To a mixture of N-p-tolylformamide (270 mg, 2.0 mmol) and4,6-dichloro-5-fluoro-2-(methylsulfonyl)pyrimidine (490 mg, 2.0 mmol) inTHF (6 mL) at 0° C. was slowly added NaOtAm (2.5 M THF solution, 0.88mL). After 30 minutes, an aqueous 2M NaOH solution (1 mL) was added andthe mixture was stirred for 30 minutes at room temperature. The reactionmixture was diluted with EtOAc (80 mL), washed with water and theorganic layer was isolated and concentrated under reduced pressure. Thecrude product was purified by column chromatography to yield4,6-dichloro-5-fluoro-N-p-tolylpyrimidin-2-amine as an off-white solid(204 mg, 38%)

Step 2. A mixture of 4,6-dichloro-5-fluoro-N-p-tolylpyrimidin-2-amine(60 mg, 0.2 mmol) and phenylenediamine (86 mg, 0.8 mmol) in DMSO (1 mL)was heated to 40° C. for 20 hours. Water (10 mL) was added to themixture. The resulting precipitate was filtered off and used in the nextstep without further purification. To the crude material in acetic acid(0.5 mL) was added triethylorthoacetate (0.5 mL). The mixture was heatedto 40° C. for 24 hours. Water (10 mL) was added to the mixture to give acrude4-chloro-5-fluoro-6-(2-methyl-1H-benzo[d]imidazol-1-yl)-N-p-tolylpyrimidin-2-amine.The crude product was filtered off and used in the next step withoutfurther purification.

Step 3. To a mixture of the crude material in DMSO (1 mL), an NH₄OHsolution (0.3 mL) was added. The mixture was heated to 100° C. for 24hours, then water (10 mL) was added to the mixture. The resultingprecipitate was filtered off, then washed with water and dried undernitrogen to yield the title compound as an off-white solid (55 mg, 79%).¹H NMR (500 MHz, Acetone-d₆) δ 8.33 (1H, s) 7.62-7.70 (3H, m) 7.39-7.45(1H, m) 7.23-7.30 (2H, m) 7.08 (2H, d, J=8.20 Hz) 6.83 (2H, br. s.) 2.63(3H, s) 2.27 (3H, s); MS m/z 349.2 [M+H]⁺.

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 6 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 565-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.88 (1H, s) 8.03 (2H, d, J= 8.51 Hz) 7.60-7.67 (1H, m) 7.57 (2H, d, J = 8.83 Hz) 7.38-7.45 (1H, m)7.22-7.29 (2H, m) 7.02 (2H, br. s) 2.62 (3H, s); MS m/z 403.1 [M + H]⁺576-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.75 (1H, s) 7.89 (2H, d, J= 8.51 Hz) 7.51-7.57 (1H, m) 7.44 (2H, d, J = 8.51 Hz) 7.24-7.30 (1H, m)7.09-7.17 (2H, m) 6.90 (2H, br. s.) 2.86 (2H, q, J = 7.46 Hz) 1.23 (3H,t, J = 7.41 Hz); MS m/z 417.2 [M + H]⁺ 585-fluoro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.77 (1H, s) 7.89 (2H, d, J = 8.51 Hz) 7.45 (2H, d, J =8.51 Hz) 7.30-7.35 (1H, m) 7.24 (1H, dd, J = 9.46, 2.21 Hz) 6.88-6.98(3H, m) 2.50 (3H, d, J = 1.26 Hz); MS m/z 421.2 [M + H]⁺ 596-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.76 (1H, s) 7.89 (2H, d, J = 8.51 Hz) 7.45 (2H, d, J =8.83 Hz) 7.23-7.33 (2H, m) 6.88-6.98 (3H, m) 2.86 (2H, q, J = 7.57 Hz)1.23 (3H, t, J = 7.41 Hz); MS m/z 434.2 [M + H]⁺ 625-fluoro-6-(2-methyl-1H-imidazo[4, 5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.59 (1H, dd, J = 4.73, 1.58 Hz) 8.19 (1H, s) 7.99 (2H, d,J = 8.83 Hz) 7.90-7.94 (1H, m) 7.71 (2H, d, J = 8.51 Hz) 7.39 (1H, dd, J= 7.88, 4.73 Hz) 6.29 (2H, br. s.) 2.82 (3H, s); MS m/z 404.2 [M + H]⁺94N²-[4-(difluoromethoxy)phenyl]-5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.59 (1H, s) 7.83-7.87 (2H,m) 7.62-7.68 (1H, m) 7.41-7.46 (1H, m) 7.24-7.31 (2H, m) 7.08-7.13 (2H,m) 6.73-7.05 (3H, m) 2.63 (3H, s); MS m/z 401.2 [M + H]⁺ 1765-fluoro-N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.13 (1H, s) 7.46-7.55 (3H, m)7.27 (1H, dt, J = 6.86, 2.40 Hz) 7.08-7.14 (2H, m) 6.62-6.72 (4H, m)3.61 (3H, s) 2.48 (3H, s); MS m/z 366.2 [M + H]⁺

Example 76-(quinolin-4-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 25)

Step 1. A mixture of4,6-dichloro-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (60 mg, 0.2mmol), quinolin-4-ylboronic acid (52 mg, 0.3 mmol), Pd(PPh₃)₄ and K₂CO₃in dioxane (1 mL) and water (0.2 mL) was heated to 100° C. for 30minutes. The resulting crude mixture was purified by columnchromatography to yield4-chloro-6-(quinolin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(34 mg, 42%).

Step 2. To a mixture of4-chloro-6-(quinolin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(34 mg, 0.08 mmol) in CH₃CN (0.5 mL), an NH₄OH solution (0.5 mL) wasadded. The mixture was stirred for 20 hours at 100° C., then water (5mL) was added to the mixture. The resulting precipitate was filteredoff, then washed with water and dried under nitrogen to yield the titlecompound as an off-white solid (22 mg, 73%). ¹H NMR (500 MHz, DMSO-d₆) δ9.66 (1H, s) 9.01 (1H, d, J=4.10 Hz) 8.28 (1H, dd, J=8.51, 0.95 Hz) 8.12(1H, d, J=7.57 Hz) 8.04 (2H, d, J=8.51 Hz) 7.83 (1H, ddd, J=8.43, 6.86,1.42 Hz) 7.60-7.68 (2H, m) 7.53 (2H, d, J=8.51 Hz) 7.01 (2H, br. s.)6.29 (1H, s); MS m/z 382.2 [M+H]⁺.

Example 86-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 45)

Step 1. To a solution of 6-chloro-2-methyl-1H-benzo[d]imidazole (612 mg,3.67 mmol) in dry DMF (4 mL) was added Cs₂CO₃ (2.4 g, 7.35 mmol). Thereaction mixture was cooled to 0° C. and4,6-dichloro-2-(methylthio)pyrimidine (1.43 g, 7.35 mmol) was added inone portion. The reaction mixture was warmed to ambient temperature andstirred for 14 hours until UPLC showed complete consumption of thestarting material. The reaction was quenched with water, and theresulting precipitate was filtered and purified by chromatography onsilica gel to provide two isomers having regiochemistry established byNOESY analysis:

5-chloro-1-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(312 mg, 26%); ¹H NMR (500 MHz, DMSO-d₆) δ 7.79 (d, J=8.8 Hz, 1H), 7.75(s, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.35 (dd, J=8.7, 2.0 Hz, 1H), 2.75 (s,3H), 2.60 (s, 3H); MS m/z 325.1, 327.1 [M+H].

6-chloro-1-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(388 mg, 32%) both as light yellow solids; ¹H NMR (500 MHz, DMSO-d₆) δ7.85 (d, J=1.9 Hz, 1H), 7.78 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.35 (dd,J=8.5, 2.2 Hz, 1H), 2.73 (s, 3H), 2.59-2.62 (m, 3H); MS m/z 325.1, 327.1[M+H].

Step 2. A mixture of6-chloro-1-(4,6-dichloropyrimidin-2-yl)-2-methyl-1H-benzo[d]imidazole(130 mg, 0.4 mmol) in CH₂Cl₂ (3 mL) was cooled to 0° C. and mCPBA (230mg, 0.8 mmol, 70% purity) was added. The reaction mixture was stirredfor 15 minutes at 0° C., then warmed to ambient temperature and stirredfor additional 30 minutes. The reaction was quenched with an solutionaqueous NaHCO₃ solution, the organic portion was separated, then driedand concentrated to provide crude6-chloro-1-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(61 mg, 43%) as a yellow solid.

Step 3. A mixture of6-chloro-1-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(61 mg, 0.17 mmol) and 4-trifluoromethoxy aniline (33 mg, 0.2 mmol) indry THF (2 mL) was cooled to −78° C., then NatOAm (2.5 M) in THF (0.15mL, 0.37 mmol) was added. The reaction mixture was stirred for 30minutes at −78° C., then quenched with water, and extracted three timeswith CH₂Cl₂. The combined organic extracts were washed with brine, driedover Na₂SO₄, then concentrated and purified by silica gel chromatographyto give4-chloro-6-(6-chloro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(46 mg, 77%) as a yellowish solid. ¹H NMR (500 MHz, Acetone-d₆) δ 9.97(br. s., 1H), 8.31 (d, J=8.5 Hz, 2H), 8.12 (d, J=2.5 Hz, 1H), 7.97 (d,J=8.5 Hz, 2H), 7.88 (d, J=8.5 Hz, 1H), 7.61 (s, 1H), 7.57 (dd, J=8.5,1.9 Hz, 1H), 3.04 (s, 3H); MS m/z 439.1 [1\4+H].

Step 4. To a mixture of4-chloro-6-(6-chloro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(46 mg, 0.11 mmol) in dioxane (2 mL), an aqueous solution of saturatedNH₄OH (2 mL) was added. The reaction mixture was heated at 100° C. in asealed tube for 16 hours until UPLC showed complete consumption ofstarting material. The crude product was precipitated by addition ofwater (five times reaction mixture volume), then filtered and purifiedby silica gel chromatography to give the title compound as an off-whitesolid (15 mg, 34%). ¹H NMR (500 MHz, Acetone-d₆) δ 8.77 (br. s., 1H),7.96 (d, J=8.5 Hz, 2H), 7.57 (d, J=1.6 Hz, 1H), 7.37-7.51 (m, 3H), 7.13(dd, J=8.5, 1.9 Hz, 1H), 6.54 (br. s., 2H), 6.22 (s, 1H), 2.57 (s, 3H);MS m/z 419 [M+H]⁺.

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 8 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 46 6-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-ol ¹H NMR (500 MHz,Acetone-d₆) δ 9.58 (br. s., 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.63 (d, J =1.9 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.14(dd, J = 8.5, 1.9 Hz, 1H), 6.09 (s, 1H), 3.81 (br. s., 1H), 2.59 (s,3H); MS m/z 420 [M + H]⁺ 476-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.77 (s, 1H), 7.96 (d, J =8.5 Hz, 2H), 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.47(d, J = 8.6 Hz, 2H), 7.12 (dd, J = 8.7, 2.0 Hz, 1H), 6.56 (br. s., 2H),6.21 (s, 1H), 2.57 (s, 3H); MS m/z 419 [M + H]⁺ 866-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.93 (br. s, 1H), 8.14 (d, J = 8.5 Hz, 2H), 7.68 (d, J =8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 1.9 Hz, 1H), 7.23(dd, J = 8.5, 1.9 Hz, 1H), 6.72 (br. s., 2H), 6.46 (s, 1H), 2.50 (s,1H), 1.23-1.33 (m, 2H), 1.11-1.17 (m, 2H); MS m/z 445 [M + H]⁺ 876-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.82 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 1.9Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.10 (dd, J= 8.5, 2.2 Hz, 1H), 6.58 (br. s., 2H), 6.33 (s, 1H), 2.22-2.44 (m, 1H),1.07-1.17 (m, 2H), 0.92-1.03 (m, 2H); MS m/z 445 [M + H]⁺ 926-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.59 (br. s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.66 (d, J =8.5 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 8.7, 2.0 Hz, 1H),7.12 (d, J = 9.1 Hz, 2H), 6.90 (t, J = 74.7 Hz, 1H), 6.61 (br. s., 2H),6.38 (s, 1H), 2.49 (ddq, J = 8.2, 4.7, 3.4 Hz, 1H), 1.26 (ddt, J = 4.7,3.4, 3.2 Hz, 2H), 1.13 (ddt, J = 8.2, 3.4, 3.2 Hz, 2H); MS m/z 443 [M +H]⁺ 93 6-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.49 (br. s, 1H), 7.77-7.85 (m, 2H), 7.59 (d, J = 1.9 Hz,1H), 7.40 (d, J = 8.5 Hz, 1H), 7.11 (dd, J = 8.5, 1.9 Hz, 1H), 6.99 (d,J = 9.1 Hz, 2H), 6.77 (t, J = 74.7 Hz, 1H), 6.46 (br. s., 2H), 6.27 (s,1H), 2.29-2.40 (m, 1H), 1.10-1.15 (m, 2H), 1.00 (ddt, J = 8.2, 3.4, 3.3Hz, 2H) ); MS m/z 443 [M + H]⁺ 966-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.90 (br. s, 1H), 8.10 (d, J= 8.2 Hz, 2H), 7.67 (d, J = 1.9 Hz, 1H), 7.57-7.65 (m, 3H), 7.27 (dd, J= 8.7, 2.0 Hz, 1H), 6.72 (br. s., 2H), 6.35 (s, 1H), 3.13 (q, J = 7.4Hz, 2H), 1.37 (t, J = 7.4 Hz, 3H); MS m/z 433 [M + H]⁺ 976-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.92 (s, 1H), 8.11 (d, J =8.5 Hz, 2H), 7.67 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.61(d, J = 8.8 Hz, 2H), 7.28 (dd, J = 8.5, 2.2 Hz, 1H), 6.73 (br. s., 2H),6.36 (s, 1H), 3.12 (q, J = 7.4 Hz, 2H), 1.37 (t, J = 7.4 Hz, 3H); MS m/z433 [M + H]⁺

Example 96-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 50)

Step 1. A mixture of6-fluoro-3-(tributylstannyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine(322 mg, 0.65 mmol), 4,6-dichloro-2-(methylthio)pyrimidine (253 mg, 1.3mmol), 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (43mg, 0.06 mmol), and bis(acetonitrile)dichloropalladium(II) (22 mg, 0.06mmol) in dioxane (2 mL) was degassed by three cycles of N₂ purging (N₂removed using vacuum). The mixture was then heated to 100° C. for 30minutes. The solution was cooled, filtered via Celite, then washed withEtOAc (3×5 mL) and concentrated. The residual material was purified bysilica gel column chromatography to afford3-(6-chloro-2-(methylthio)pyrimidin-4-yl)-6-fluoro-2-(trifluoromethyl)imidazol[1,2-a]pyridine(137 mg, 58% yield) as yellowish solid. ¹H NMR (500 MHz, Acetone-d₆) δ9.29 (ddd, J=5.0, 2.5, 0.9 Hz, 1H), 7.92 (ddd, J=10.1, 5.0, 0.8 Hz, 1H),7.71 (ddd, J=10.0, 7.8, 2.5 Hz, 1H), 7.54 (d, J=0.8 Hz, 1H), 2.67 (s,3H); MS m/z 363.1 [M+H].

Step 2. To a solution of3-(6-chloro-2-(methylthio)pyrimidin-4-yl)-6-fluoro-2-(trifluoromethyl)imidazol[1,2-a]pyridine(137 mg, 0.377 mmol) in ACN (10 mL) was added KMnO₄ (89 mg, 0.566 mmol)and 4N H₂SO₄ (1 mL, 2 mmol). The reaction mixture was stirred at ambienttemperature for 10 minutes, then quenched with a saturated aqueousNaHSO₃ solution, neutralized with KOAc to about pH 7 and extracted threetimes with EtOAc. The combined organic portions were dried over Na₂SO₄,then concentrated to provide3-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridine(121 mg, 82%) as a brown solid.

Step 3. A mixture of3-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-6-fluoro-2-(trifluoromethyl)imidazol[1,2-a]pyridine(61 mg, 0.154 mmol) and 4-trifluoromethoxy aniline (30 mg, 0.185 mmol)in dry THF (2 mL) was cooled to 0° C., then NatOAm (2.5 M) in THF (0.14mL, 0.34 mmol) was added. The reaction mixture was stirred for 30minutes at 0° C., then quenched with water and extracted three timeswith CH₂Cl₂. The combined organic extracts were washed with brine, driedover Na₂SO₄, then concentrated and purified by silica gel chromatographyto give4-chloro-6-(6-fluoro-2-(trifluoromethyl)imidazol[1,2-a]pyridin-3-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(41 mg, 56%) as white solid. ¹H NMR (500 MHz, Acetone-d₆) δ 9.76 (br.s., 1H), 9.41 (dd, J=5.0, 2.4 Hz, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.91(ddd, J=10.1, 5.0, 0.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.69 (ddd,J=10.0, 7.8, 2.5 Hz, 1H), 7.29 (d, J=0.9 Hz, 1H); MS m/z 476.2 [M+H].

Step 4. To a mixture of4-chloro-6-(6-fluoro-2-(trifluoromethyl)imidazol[1,2-a]pyridin-3-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(41 mg, 0.09 mmol) in ACN (2 mL) was added an aqueous saturated NH₄OHsolution (2 mL). The reaction mixture was heated at 100° C. in a sealedtube for 5 hours until UPLC showed complete consumption of startingmaterial. The resulting crude product was precipitated by addition ofwater (five times reaction mixture volume), then filtered and dried togive the title compound as a white solid (20 mg, 51%). ¹H NMR (500 MHz,Acetone-d₆) δ 9.30 (ddd, J=5.4, 2.5, 0.9 Hz, 1H), 8.92 (br. s, 1H), 8.10(d, J=8.5 Hz, 2H), 7.82 (ddd, J=10.1, 5.4, 0.9 Hz, 1H), 7.48-7.63 (m,3H), 6.68 (br. s., 2H), 6.51 (d, J=0.9 Hz, 1H); MS m/z 457 [M+H]⁺

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 9 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 48 6-(6-fluoro-2-methylimidazo[1,2-a]pyrimidin-3-yl)-N²-[4- (trifluoromethyl)phenyl]pyrimidine-2,4-diamine MS m/z 404.3 [M + H]⁺ 55N²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3- yl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ9.15 (ddd, J = 5.0, 2.5, 0.9 Hz, 1H), 8.44 (br. s, 1H), 7.70-7.82 (m,2H), 7.66 (ddd, J = 10.0, 5.3, 0.8 Hz, 1H), 7.43 (ddd, J = 10.0, 8.2,2.5 Hz, 1H), 6.94-7.02 (m, 2H), 6.75 (t, J = 75.0 Hz, 1H), 6.43 (br. s.,2H), 6.30 (s, 1H); MS m/z 455 [M + H]⁺

Example 106-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 82)

Step 1. A mixture of 1-aminopyridinium iodide (9.59 g, 43.2 mmol) andethyl but-2-ynoate (5.2 mL, 51.83 mmol) in DMF (50 mL) were cooled to 0°C., then K₂CO₃ (11.94 g, 86.4 mmol) was added. The reaction mixture waswarmed to room temperature and stirred for 3 days until UPLC showedcomplete conversion of the starting material. The reaction mixture wasportioned between water and EtOAc. The organic portion was concentrated,then MeOH (50 mL) and NaOH (6 mL, 50% in H₂O) were added and thereaction mixture was heated at 70° C. for one hour. The MeOH wasevaporated and the remaining mixture was acidified with 1N HCl to aboutpH 4. The resulting 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acidwas isolated on a filter and dried under vacuum.

Step 2. The solid from Step 1 was dissolved in MeOH (50 mL) and CHCl₃(100 mL), then N-iodosuccinimide (7.3 g, 32.4 mmol) was added in oneportion. The reaction mixture was stirred for 20 minutes at roomtemperature. The MeOH was evaporated and the residue was washed threetimes with an aqueous solution of NaHCO₃. The organic portions weredried over Na₂SO₄, the solvent was removed under reduced pressure, andthe crude product was purified by silica gel chromatography to give3-iodo-2-methylpyrazolo[1,5-a]pyridine (4.2 g, 38% over 3 steps) as anoff-white solid. ¹H NMR (500 MHz, Acetone-d₆) δ 8.51 (dt, J=6.8, 1.3 Hz,1H), 7.41 (dt, J=8.8, 1.3 Hz, 1H), 7.31 (ddd, J=8.8, 6.8, 1.3 Hz, 1H),6.90 (td, J=6.8, 1.3 Hz, 1H), 2.42 (s, 3H); MS m/z 298.1 [M+H].

Step 3. To 3-iodo-2-methylpyrazolo[1,5-a]pyridine (780 mg, 3.02 mmol) inTHF (5 mL) was added isopropylmagnesium chloride lithium chloridecomplex solution (1.3 M in THF, 3.5 mL, 4.5 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 20 min, then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.68 g, 9.07 mmol)was added in one portion. The mixture was stirred at 0° C. for 20minutes until UPLC showed complete consumption of the starting material.The mixture was then partitioned between ethyl acetate and water. Theorganic phase was washed with brine, then dried over Na₂SO₄ andconcentrated. The residual material was purified by silica gelchromatography to afford2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(587 mg, 75%) as a clear solid. ¹H NMR (500 MHz, Acetone-d₆) δ 8.52 (dt,J=6.9, 1.1 Hz, 1H), 7.85 (dt, J=8.8, 1.1 Hz, 1H), 7.28 (ddd, J=8.8, 6.8,1.1 Hz, 1H), 6.88 (td, J=6.9, 1.4 Hz, 1H), 2.52 (s, 3H), 1.37 (s, 12H);MS m/z 259.1 [M+H].

Step 4. A mixture of2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(32 mg, 0.124 mmol), di-tert-butyl2-chloro-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate(90 mg, 0.186 mmol), tris(dibenzylideneacetone) dipalladium(0) (11 mg,0.012 mmol), tricyclohexylphosphine (9 mg, 0.031 mmol), tribasicpotassium phosphate (537.0 mg, 0.248 mmol) in dioxane (2.5 mL) and water(0.05 mL) was degassed by purging with Argon. The mixture was heated to85° C. for 2 hours, then cooled and filtered via a Celite plug. Thefiltrate was concentrated and purified by silica gel columnchromatography to give tert-butyl3,3-dimethylbutanoyl(2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yl)carbamate (49 mg, 68%) as a clear oil. Theintermediate was dissolved in dichloromethane (1 mL) and treated withTFA (0.1 mL) at 0° C. The resulting mixture was stirred at ambienttemperature for 30 min and the solvent was evaporated. The residualmaterial was partitioned between ethyl acetate and saturated NaHCO₃. Theorganic layer was separated, then dried over Na₂SO₄, filtered andconcentrated. The product was purified by silica gel chromatography toafford the title compound as an off white solid (12 mg, 31%). ¹H NMR(500 MHz, Acetone-d₆) δ 8.62 (br. s., 1H), 8.47 (dt, J=6.9, 1.1 Hz, 1H),8.36 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H),7.24 (ddd, J=9.0, 6.8, 0.9 Hz, 1H), 6.87 (td, J=6.9, 1.4 Hz, 1H), 6.42(s, 1H), 6.12 (br. s., 2H), 2.60 (s, 3H); MS m/z 385 [M+H]⁺

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 10 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 90 6-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4- diamine¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (br. s., 1H), 8.69 (d, J = 6.9 Hz, 1H),8.31 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz,2H), 7.35 (dd, J = 8.2, 7.3 Hz, 1H), 6.96 (td, J = 6.8, 1.6 Hz, 1H),6.65 (br. s., 2H), 6.31 (s, 1H), 3.08 (q, J = 7.6 Hz, 2H), 1.34 (t, J =7.4 Hz, 3H); MS m/z 399 [M + H]⁺ 91N²-[4-(difluoromethoxy)phenyl]-6-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2, 4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.39 (dt, J = 6.9, 0.9 Hz, 1H), 8.19 (dt, J = 8.8, 0.9 Hz, 1H), 8.12(br. s., 1H), 7.74-7.82 (m, 2H), 7.13 (ddd, J = 9.0, 6.8, 0.9 Hz, 1H),6.93- 7.00 (m, 2H), 6.78 (td, J = 6.6, 1.8 Hz, 1H), 6.74 (t, J = 75.0Hz, 1H), 6.26 (s, 1H), 5.92 (br. s., 2H), 2.98 (q, J = 7.5 Hz, 2H), 1.22(t, J = 7.6 Hz, 3H); MS m/z 397 [M + H]⁺ 98N²-[4-(trifluoromethyl)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3- yl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.57 (dt, J = 6.9, 0.9 Hz, 1H), 8.54 (br. s, 1H), 8.21 (dt, J = 9.1, 0.9Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.34 (ddd,J = 9.1, 6.8, 1.1 Hz, 1H), 7.07 (td, J = 6.9, 1.3 Hz, 1H), 6.30 (s, 1H),6.24 (br. s., 2H); MS m/z 439 [M + H]⁺ 1096-(5-fluoro-2-methylpyrazolo[1, 5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.78 (br. s., 1H), 8.59 (ddd, J = 7.6, 5.4, 0.9 Hz, 1H),8.22 (dd, J = 10.4, 2.8 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.59 (d, J =8.5 Hz, 2H), 6.89 (td, J = 7.3, 2.8 Hz, 1H), 6.49 (s, 1H), 6.20 (br. s.,2H), 2.66 (s, 3H); MS m/z 403 [M + H]⁺ 1134-chloro-6-(5-methoxy-2-methylpyrazolo[1, 5-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine ¹H NMR (500 MHz, Acetone-d₆) δ9.23 (br. s, 1H), 8.47 (dd, J = 7.6, 0.6 Hz, 1H), 8.05 (d, J = 8.5 Hz,2H), 7.78 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.16 (s, 1H),6.72 (dd, J = 7.6, 2.8 Hz, 1H), 3.83 (s, 3H), 2.69 (s, 3H); MS m/z 434[M + H]⁺ 114 6-(5-methoxy-2-methylpyrazolo[1, 5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.52 (br. s., 1H), 8.37 (d, J = 7.3 Hz, 1H), 8.11 (d, J =8.5 Hz, 2H), 7.73 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 6.60(dd, J = 7.3, 2.8 Hz, 1H), 6.44 (s, 1H), 6.09 (br. s., 2H), 3.82 (s,3H), 2.60 (s, 3H); MS m/z 415 [M + H]⁺ 1206-(5-amino-2-methylpyrazolo[1, 5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.30 (br. s., 1H), 8.04 (dd, J = 7.3, 0.6 Hz, 1H), 8.00(d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 1.9 Hz, 1H),6.34 (dd, J = 7.3, 2.5 Hz, 1H), 6.20 (s, 1H), 5.85 (br. s., 2H), 5.11(br. s., 2H), 2.40 (s, 3H); MS m/z 400 [M + H]⁺ 1216-(5-chloro-2-methylpyrazolo[1, 5-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.54 (ddd, J = 4.7, 2.2, 0.9 Hz, 2H), 8.35 (br. s, 1H),7.84-8.00 (m, 2H), 7.08-7.20 (m, 2H), 6.94 (dd, J = 7.6, 2.2 Hz, 1H),6.89 (t, J = 74.4 Hz, 1H), 6.44 (s, 1H), 6.09 (br. s., 2H), 2.65 (s,3H); MS m/z 417 [M + H]⁺ 122 6-(5-chloro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4- (trifluoromethyl)phenyl]pyrimidine-2, 4-diamine¹H NMR (500 MHz, Acetone-d₆) δ 8.72 (br. s, 1H), 8.51-8.59 (m, 2H), 8.09(d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 6.95 (dd, J = 7.3, 2.5Hz, 1H), 6.50 (s, 1H), 6.20 (br. s., 2H), 2.66 (s, 3H); MS m/z 419 [M +H]⁺ 124 6-(5-chloro-2-ethylpyrazolo[1, 5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.56 (br. s, 1H), 8.42 (dd, J = 7.3, 0.6 Hz, 1H), 8.33(dd, J = 2.5, 0.6 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.8Hz, 2H), 6.80 (dd, J = 7.4, 2.4 Hz, 1H), 6.33 (s, 1H), 6.07 (br. s.,2H), 2.97 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H); MS m/z 433 [M +H]⁺ 125 6-(5-chloro-2-ethylpyrazolo[1, 5-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.41 (dd, J = 7.6, 0.9 Hz, 1H), 8.32 (dd, J = 2.5, 0.6 Hz,1H), 8.19 (br. s., 1H), 7.73-7.78 (m, 2H), 6.96-7.01 (m, 2H), 6.79 (dd,J = 7.4, 2.4 Hz, 1H), 6.74 (t, J = 75.0 Hz, 1H), 6.27 (s, 1H), 5.96 (br.s., 2H), 2.96 (q, J = 7.4 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H); MS m/z 431[M + H]⁺

Example 116-(2-ethyl-6-fluoro-1-H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 26)

Step 1. A mixture of 2,6-dichloropyrimidine-4-amine (3.78 g, 23.05mmol), DMAP (catalytic) in dichloromethane (20 mL) was treated withdi-tert-butyldicarbonate (11.05 g, 50.71 mmol) at 0° C. After theaddition, the mixture was stirred at ambient temperature overnight, thenpoured into ice-water (120 mL) and extracted with dichloromethane (150mL). The organic phase was separated, washed with brine (100 mL), driedover MgSO₄, then filtered and the remaining liquid evaporated. Theresidual material was separated by a pad of silica gel (150 g) to afforddi-tert-butyl (2,6-dichloropyrimidin-4-yl)imidodicarbonate as an oil(7.55 g, 90% yield).

Step 2. A solution of di-tert-butyl(2,6-dichloropyrimidin-4-yl)imidodicarbonate (1.75 g, 4.81 mmol),4-trifluoromethylaniline (775.0 mg, 4.81 mmol) in THF (10 mL) wastreated with potassium tert-butoxide solution (1M in THF, 9.62 mL, 9.62mmol) at −78° C. The mixture was allowed to stir and warm to 0° C. over20 minutes, then poured into ice-water (120 mL) and extracted withdichloromethane (150 mL). The organic phase was separated, washed withbrine (100 mL), dried over MgSO₄, then filtered and the remaining liquidevaporated. The residual material was separated by silica gel columnchromatography, eluting with hexane and 2% ethyl acetate-hexane toafford di-tert-butyl6-chloro-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate(750.0 mg, 32% yield), then eluting with 4% ethyl acetate-hexane toafford di-tert-butyl2-chloro-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate(1.08 g, 46% yield).

Step 3. A mixture of di-tert-butyl2-chloro-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate(393.0 mg, 0.80 mmol), 5-fluoro-2-nitroaniline (125.5 mg, 0.80 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 38.4 mg,0.08 mmol), tris(dibenzylideneacetone) dipalladium(0) (37.0 mg, 0.04mmol) and tribasic potassium phosphate (512.0 mg, 2.4 mmol) in dioxane(2 mL) was degassed by three cycles of vacuum pumping and N₂ purging,then heated to 100° C. for 4 hours. The solution was cooled and pouredinto water (20 mL), then extracted with dichloromethane. The extract wasdried over MgSO₄, filtered and the remaining liquid evaporated. Theresidual material was separated by silica gel column chromatography,eluting with 1:1 dichloromethane-hexane, then 1:2 ethylacetate-dichloromethane to afford di-tert-butyl6-(5-fluoro-2-nitrophenylamino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate(760.0 mg, 80% yield).

Step 4. A pressure reaction vessel charged with di-tert-butyl6-(5-fluoro-2-nitrophenylamino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate(300.0 mg, 0.49 mmol), Pd/C (10%, wet, 30.0 mg) and 1:1 ethylacetate-methanol (5 mL) was placed on a Parr shaker. The mixture wasdegassed by three cycles of vacuum pumping and N₂ purging. The vesselwas filled with hydrogen (45 psi) and placed on the Parr shaker for 2hours. The charcoal was filtered off and the solvent was evaporated toprovide di-tert-butyl6-(2-amino-5-fluorophenylamino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonateas a residue which was used in the next step without furtherpurification.

Step 5. A mixture of di-tert-butyl6-(2-amino-5-fluorophenylamino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate(285.0 mg, 0.49 mmol), 1,1,1-triethoxypropane (173.0 mg, 0.98 mmol),p-toluenesulfonic acid (5.0 mg, 0.025 mmol) and ethanol (2.0 mL) washeated to reflux for 3 hours. After cooling, the mixture was partitionedbetween dichloromethane (20 mL) and a saturated NaHCO₃ solution (10 mL).The organic phase was washed with brine (10 mL), dried over MgSO₄, thenfiltered and the remaining liquid evaporated. The residual oil wastriturated with ethyl ether to afford the title compound (128.0 mg, 63%yield). m.p. 236-238° C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.00(d, J=8.20 Hz, 2H), 7.63-7.71 (m, 1H), 7.58 (d, J=8.20 Hz, 2H), 7.40(td, J=1.00, 12.61 Hz, 1H), 7.18 (br. s, 2H), 7.06-7.15 (m, 1H), 6.18(s, 1H), 2.96-3.11 (m, 2H), 1.31 (t, J=7.41 Hz, 3H). MS (ES+) m/e 417.3(100)

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 11 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 5N²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (br. s.,1H), 7.79 (d, J = 8.20 Hz, 2H), 7.67 (dd, J = 4.57, 8.35 Hz, 1H), 7.50(d, J = 8.20 Hz, 1H), 6.88-7.31 (m, 6H), 6.95-7.25 (t, J = −75.00 Hz,1H), 2.69 (s, 3H); m.p.: 141-143° C.; MS m/z 401.5 [M + H]⁺ 10N²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.58 (s, 1H),8.05 (d, J = 12.61 Hz, 1H), 7.63 (dd, J = 4.89, 8.67 Hz, 1H), 7.40-7.52(m, 2H), 7.22-7.28 (m, 1H), 6.96-7.21 (t, J = 62.50 Hz, 1H), 7.08-7.20(m, 3H), 6.16 (s, 1H), 2.66 (s, 3H); MS m/z 419.0 [M + H]⁺ 11N²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.56 (s, 1H),7.96-8.14 (m, 1H), 7.65 (dd, J = 5.04, 8.83 Hz, 1H), 7.42-7.47 (m, 1H),7.38 (dd, J = 2.52, 9.46 Hz, 1H), 6.96-7.25 (t, J = 72.50 Hz, 1H), 7.24(d, J = 13.87 Hz, 1H), 7.16 (br. s., 2H), 7.06-7.13 (m, 1H), 6.14 (s,1H), 2.98-3.07 (m, 2H), 1.30 (t, J = 7.41 Hz, 3H); m.p.: 159-161° C.; MSm/z 433.0 [M + H]⁺ 71N²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (s, 1H),7.78 (d, J = 9.14 Hz, 2H), 7.58-7.70 (m, 1H), 7.32-7.41 (m, 1H),6.95-7.25 (t, J = 75.00 Hz, 1H), 7.01-7.16 (m, 5H), 6.09 (s, 1H),2.90-3.11 (m, 2H), 1.28 (t, J = 7.41 Hz, 3H); m.p.: 171-173° C.; MS m/z415.4 [M + H]⁺; MS (ES+) m/e (100), 416.4 (30)

Example 126-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 27)

Step 1. To a solution of tert-butyl6-(2-amino-5-fluorophenylamino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-ylcarbamate(212.0 mg, 0.37 mmol), triethylamine (42.0 mg, 0.41 mmol) indichloromethane (2 mL) was added cyclopropanecarbonyl chloride (38.3 mg,0.37 mmol) at 0° C. After the addition, the mixture was stirred atambient temperature for 3 hours, then partitioned betweendichloromethane and water. The organic phase was washed with brine,dried over MgSO₄, then filtered and the remaining liquid evaporated. Theresidual solid was used directly in the next step without furtherpurification.

Step 2. A mixture of tert-butyl6-(2-(cyclopropanecarboxamido)-5-fluorophenylamino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-ylcarbamate(amount needed), 4-methylbenzenesulfonic acid (7.0 mg, 0.037 mmol) andacetonitrile (3 mL) was heated in a microwave oven at 180° C. for 30min. The mixture was partitioned between ethyl acetate and a saturatedNaHCO₃ solution. The organic phase was washed with brine, dried overMgSO₄, then filtered and the remaining liquid evaporated. The residualmaterial was separated by silica gel column chromatography, eluting with1:1 dichloromethane-hexane, then 1:5 MeOH:EtOAc (50%) in DCM to affordthe title compound (35.0 mg, 22% yield in two steps). m.p. 246-248° C.¹H NMR (500 MHz, DMSO-d₆) δ 9.63-9.83 (m, 1H), 7.85-8.12 (d, J=8.20 Hz,2H), 7.52-7.62 (m, 3H), 7.40-7.50 (m, 1H), 7.21 (br. s, 2H), 7.02-7.13(m, 1H), 6.27 (s, 1H), 2.30-2.46 (m, 1H), 1.13-1.18 (m, 2H), 1.08-1.12(m, 2H). MS (ES+) m/e 429.2 (100), 430.2 (20).

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 12 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 126-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.61(s, 1H), 8.10 (dd, J = 2.21, 13.87 Hz, 1H), 7.56 (dd, J = 5.04, 8.83 Hz,1H), 7.40-7.50 (m, 2H), 7.20-7.28 (m, 1H), 6.96-7.26 (t, J = 72.50 Hz,1H), 7.18 (br. s., 2H), 7.05-7.10 (m, 1H), 6.25 (s, 1H), 2.31-2.44 (m,1H), 1.13-1.20 (m, 2H), 1.11 (m, 2H); m.p.: 185-186° C.; MS m/z 445.5[M + H]⁺ 33 6-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,DMSO-d₆) δ 9.72 (s, 1H), 7.98 (d, J = 8.51 Hz, 2H), 7.91 (dd, J = 4.89,8.98 Hz, 1H), 7.54-7.75 (t, J = 52.50 Hz, 1H), 7.56-7.64 (m, 3H),7.18-7.36 (m, 3H), 6.30 (s, 1H); m.p.: 201-203° C.; MS m/z 439.4 [M +H]⁺ 696-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.14 (d, J = 8.83Hz, 2H), 8.03 (d, J = 7.88 Hz, 1H), 7.72-7.93 (t, J = 52.50 Hz, 1H),7.91 (d, J = 8.20 Hz, 1H), 7.73 (d, J = 8.83 Hz, 2H), 7.61-7.67 (m, 1H),7.55-7.61 (m, J = 6.90 Hz, 1H), 7.44 (br. s, 2H), 6.46 (s, 1H); m.p.:186-189° C.; MS m/z 439.4 [M + H]⁺ 706-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,DMSO-d₆) δ 9.39 (s, 1H), 7.83 (d, J = 9.14 Hz, 2H), 7.54-7.60 (m, 1H),7.39-7.47 (m, 1H), 6.98-7.27 (t, J = 72.50 Hz, 1H), 7.08 (s, 5H), 6.21(s, 1H), 2.34- 2.45 (m, 1H), 1.14-1.18 (m, 2H), 1.07-1.13 (m, 2H); m.p.:177-179° C.; MS m/z 427.4 [M + H]⁺ 72N²-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (s, 1H),7.88-7.95 (m, 1H), 7.79 (d, J = 9.14 Hz, 2H), 7.55-7.76 (t, J = 52.50Hz, 1H), 7.58-7.63 (m, 1H), 7.29-7.35 (m, 1H), 6.98- 7.27 (t, J = 72.50Hz, 1H), 7.18 (br. s., 2H), 7.09 (d, J = 9.14 Hz, 2H), 6.23 (s, 1H);m.p.: 143-145° C.; MS m/z 437.4 [M + H]⁺ 736-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.00 (d, J = 8.83Hz, 2H), 7.72-7.75 (m, 1H), 7.68-7.71 (m, 1H), 7.57 (d, J = 8.83 Hz,2H), 7.33 (dt, J = 1.26, 8.04 Hz, 2H), 7.18 (br. s, 2H), 6.27 (s, 1H),4.84 (s, 2H), 3.27 (s, 3H); m.p.: 209-211° C.; MS m/z 415.4 [M + H]⁺ 746-[2-(propan-2-yl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4- diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.00 (d, J = 8.83Hz, 2H), 7.64-7.68 (m, 1H), 7.56 (d, J = 8.83 Hz, 2H), 7.44-7.49 (m,1H), 7.22-7.27 (m, 2H), 7.18-7.22 (s, br, 2H), 6.16 (s, 1H), 3.58-3.66(m, 1H), 1.30 (d, J = 6.94 Hz, 6H); m.p.: 168-171° C.; MS m/z 413.4 [M +H]⁺ 78N²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(methoxymethyl)-1H-benzimidazol-1-yl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (br. s.,1H), 7.66-8.01 (m, 3H), 7.53 (d, J = 6.31 Hz, 1H), 6.83-7.36 (m, 5H),6.96-7.26 (t, J = 75.00 Hz, 1H), 6.20 (br. s., 1H), 4.79 (br. s., 2H),3.27 (s, 3H); m.p.: 120-122° C.; MS m/z 431.3 [M + H]⁺ 79N²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (s, 1H),7.78 (d, J = 8.83 Hz, 2H), 7.65 (dd, J = 5.04, 8.83 Hz, 1H), 6.95-7.25(t, J = 75.00 Hz, 1H), 7.23-7.33 (m, 1H), 7.01-7.17 (m, 5H), 6.08 (s,1H), 3.50-3.72 (m, 1H), 1.28 (d, J = 6.94 Hz, 6H); m.p.: 167-169° C.; MSm/z 429.5 [M + H]⁺ 806-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,DMSO-d₆) δ 9.41 (s, 1H), 7.82 (d, J = 9.14 Hz, 2H), 7.52-7.63 (m, 1H),7.34-7.43 (m, 1H), 6.97-7.26 (t, J = 72.50 Hz, 1H), 7.03-7.16 (m, 5H),6.18 (s, 1H), 2.36-2.45 (m, 1H), 1.15-1.21 (m, 2H), 1.09-1.14 (m, 2H);m.p.: 136-138° C.; MS m/z 427.3 [M + H]⁺ 81N²-[4-(difluoromethoxy)phenyl]-6-[5-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (s, 1H),7.80 (d, J = 8.83 Hz, 2H), 7.47 (dd, J = 5.04, 8.83 Hz, 1H), 6.95-7.25(t, J = 75.00 Hz, 1H), 7.23-7.33 (m, 1H), 7.01-7.17 (m, 5H), 6.09 (s,1H), 3.50-3.72 (m, 1H), 1.48 (d, J = 6.94 Hz, 6H); m.p.: 118-120° C.; MSm/z 429.5 [M + H]⁺ 88N²-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.36 (s, 1H),7.87 (d, J = 8.20 Hz, 1H), 7.72-7.81 (m, 3H), 7.56-7.76 (t, J = 50.00Hz, 1H), 7.46-7.51 (m, 1H), 7.40-7.45 (m, 1H), 6.96- 7.26 (t, J = 75.00Hz, 1H), (7.17 (br. s., 2H), 7.07 (d, J = 8.83 Hz, 3H); m.p.: 114-115°C.; MS m/z 419.4 [M + H]⁺ 89N²-[4-(difluoromethoxy)phenyl]-6-[2-(propan-2-yl)-1H-benzimidazol-1-yllpyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.36 (s, 1H), 7.77 (d, J = 9.77Hz, 2H), 7.60-7.68 (m, 1H), 7.42-7.49 (m, 1H), 7.18-7.28 (m, 2H),6.94-7.27 (t, J = 75.00 Hz, 1H), 7.04 (m, 4H), 6.08 (s, 1H), 3.52-3.68(m, 1H), 1.29 (d, J = 6.62 Hz, 6H); m.p.: 184-187° C.; MS m/z 411.4 [M +H]⁺ 103 6-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine m.p.: 237-238° C.; MSm/z 429.4 [M + H]⁺

Example 136-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 4)

Step 1. To 4-fluorobenzene-1,2-diamine (13.88 g, 110.04 mmol) was addeddi-tert-butyldicarbonate (50 mL) at 0° C. The resulting mixture wasstirred at ambient temperature for 5 min, then diluted with ice-water(500 mL) and extracted with 1:1 ethyl acetate-hexane (500 mL). Theorganic phase was washed with brine (300 mL), dried over MgSO₄, thenfiltered and the remaining liquid evaporated. The residual solid waswashed with hexane to afford tert-butyl(2-amino-4-fluorophenyl)carbamate (17.0 g, 69% yield). ¹H NMR (500 MHz,Acetone-d₆) δ 7.48 (br. s, 1H), 7.05-7.26 (m, 1H), 6.51-6.59 (m, 1H),6.27-6.38 (m, 1H), 4.80 (s, 2H), 1.47 (s, 9H).

Step 2a. A mixture of tert-butyl (2-amino-4-fluorophenyl)carbamate (17.0g, 74.80 mmol) and 4,6-dichloro-2-(methylsulfonyl)pyrimidine (22.1 g,97.2 1 mmol) in DMSO (100 mL) was stirred at ambient temperatureovernight. The mixture was poured into a cold saturated NaHCO₃ solution(500 mL) and extracted with ethyl acetate (500 mL). The organic phasewas washed twice with water (500 mL) and brine (300 mL), then dried overMgSO₄ and filtered through a pad of silica gel (300 mg). The solvent wasevaporated and the residue was used directly in the next step withoutfurther purification.

Step 2b. The residue in dichloromethane (300 mL) was treated with TFA(100 mL) at 0° C. The resulting mixture was stirred at ambienttemperature for 2 hours. The mixture was condensed via rotavap and theresidue was partitioned between ethyl acetate (500 mL) and a saturatedNaHCO₃ solution (400 mL). The organic phase was washed with water (300mL) and brine (300 mL), dried over MgSO₄, then filtered and theremaining liquid evaporated. The residual solid was washed with ethylether to affordN²-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-4-fluorobenzene-1,2-diamine(19.5 g, 81% yield). MS (ES+) m/e 317.1 (100), 319.2 (60).

Step 3. A mixture ofN²-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-4-fluorobenzene-1,2-diamine(14.5 g, 45.89 mmol), 1,1,1-triethoxyethane (22.1 g, 138.10 mmol) inacidic acid (50 mL) and acetonitrile (70 mL) was stirred at ambienttemperature overnight. The mixture was slowly added into a coldsaturated NaHCO₃ solution (500 mL) to afford a solid, which wascollected by filtration. The solid was washed with water (500 mL), thenacetonitrile (300 mL). The solid was dried in vacuo to afford1-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-6-fluoro-2-methyl-1H-benzimidazole(13.6 g, 87% yield). MS (ES+) m/e 341.1 (100), 343.1 (80).

Step 4. A suspension of1-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-6-fluoro-2-methyl-1H-benzimidazole(12.97 g, 38.06 mmol), 4-(trifluoromethyl)aniline (6.13 g, 38.07 mmol)and a 1:4 solution of DMF:THF (80 mL) was treated with sodiumtert-pentoxide (2.5 M solution in THF) at −78° C. The mixture wasstirred at −78° C. for 5 minutes, then at −10° C. for 15 minutes. Themixture was poured into ice-water (600 mL) to afford a solid. The solidwas collected by filtration, washed with water (300 mL), thenacetonitrile (200 mL) and hexane (200 mL) and dried in vacuo to afford4-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine(13.6 g, 85% yield). MS (ES+) m/e 422.0 (70), 424.2 (100).

Step 5. A mixture of4-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine(10.25 g, 48.79 mmol) and DMSO (80 mL) was placed in a 350 mL pressurebottle. The mixture was treated with ammonium hydroxide (28-30%, 7 mL)at 60° C. for a period of 5 minutes. After the addition, the bottle wassealed and the mixture was stirred at 80° C. overnight. The mixture wascooled, then partitioned between ethyl acetate (500 mL) and water (500mL). The organic phase was washed twice with water (300 mL), then brine(300 mL), dried over MgSO₄, then filtered and the remaining liquidevaporated. The residual material was washed with acetonitrile and driedin vacuo to afford the title compound as a white solid (8.32 g, 85%yield). m.p. 234-236° C. ¹H NMR (500 MHz, Acetone-d₆) δ 8.93 (s, 1H),8.09 (d, J=8.51 Hz, 2H), 7.54-7.64 (m, 3H), 7.44 (dd, J=2.52, 9.46 Hz,1H), 6.97-7.09 (m, 1H), 6.69 (br. s., 2H), 6.35 (s, 1H), 2.69 (s, 3H).MS (ES+) m/e 403.3 (100), 404.3 (70).

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 13 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 1046-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.87 (s, 1H), 8.09 (d, J =8.51 Hz, 2H), 7.53-7.73 (m, 3H), 7.36 (dd, J = 2.52, 9.46 Hz, 1H), 7.05(dt, J = 2.52, 9.30 Hz, 1H), 6.68 (br. s., 2H), 6.33 (s, 1H), 3.10 (q, J= 7.57 Hz, 2H), 1.36 (t, J = 7.41 Hz, 3H); m.p.: 236- 237° C.; MS m/z418.3 [M + H]⁺ 105N²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine m.p.: 172-173° C.; MS m/z 419.3 [M + H]⁺

Example 146-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine(Cpd 133)

Step 1. A solution of 4-fluoro-2-nitroaniline (8.27 g, 51.43 mmol) indichloromethane (50 mL) was treated with di-tert-butyldicarbonate (24.7g, 113.15 mmol) via an addition funnel. After the addition, the mixturewas stirred at ambient temperature overnight, then partitioned betweendichloromethane and water. The organic phase was washed with brine,dried over MgSO₄, then filtered and the remaining liquid evaporated. Theresidual solid was washed with hexane to afford di-tert-butyl4-fluoro-2-nitrophenyliminodicarbonate (15.0 g, 89% yield).

Step 2. A mixture of di-tert-butyl4-fluoro-2-nitrophenyliminodicarbonate (15.0 g, 42.13 mmol), NaOH (6.74g, 168.5 mmol), THF (50 mL) and water (50 mL) was stirred at 70° C.overnight. The THF was evaporated via rotovap and the residual materialwas diluted with water (200 mL). The solid was collected by filtration,washed with 0.5N HCl and water, then dried to give tert-butyl4-fluoro-2-nitrophenylcarbamate (10.43 g, 95% yield).

Step 3. A pressure reaction vessel charged with tert-butyl4-fluoro-2-nitrophenylcarbamate (7.23 g, 28.2 mmol), Pd/C (10%, wet,723.0 mg) and methanol (30 mL) was placed on a Parr shaker. The mixturewas degassed by three cycles of vacuum pumping and N₂ purging. Thevessel was filled with hydrogen (45 psi) and placed on the Parr shakerfor 2 hours. The charcoal was filtered off and the solvent wasevaporated from the residual tert-butyl 2-amino-4-fluorophenylcarbamate,used in the next step without further purification.

Step 4. A mixture of tert-butyl 2-amino-4-fluorophenylcarbamate (2.70 g,11.95 mmol), 4,6-dichloro-2-(methylsulfonyl)pyrimidine (2.71 g, 11.95mmol) and DMSO (15 mmol) was stirred at ambient temperature overnight.The mixture was partitioned between ethyl acetate and water. The organicphase was washed twice with water, then brine, dried over MgSO₄, thenfiltered and the remaining liquid evaporated. The residual tert-butyl2-(6-chloro-2-(methylsulfonyl)pyrimidin-4-ylamino)-4-fluorophenylcarbamatewas used directly in the next step.

Step 5. A solution of the residual tert-butyl2-(6-chloro-2-(methylsulfonyl)pyrimidin-4-ylamino)-4-fluorophenylcarbamatein dichloromethane (20 mL) was treated with TFA (5 mL) at 0° C. Theresulting mixture was stirred at ambient temperature for 2 hours. Themixture was condensed via rotavap and the residue was partitionedbetween ethyl acetate (100 mL) and a saturated NaHCO₃ solution (100 mL).The organic phase was washed with water (100 mL) followed by brine (100mL), dried over MgSO₄, then filtered and the remaining liquidevaporated. The residual solid was triturated with ethyl ether to affordN²-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-4-fluorobenzene-1,2-diamine(3.46 g, 92% yield).

Step 6. A mixture ofN²-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-4-fluorobenzene-1,2-diamine(1.35 g, 5.65 mmol), 1,1,1-triethoxyethane (3.62 g, 22.59 mmol) inacidic acid (3 mL) and acetonitrile (10 mL) was stirred at ambienttemperature overnight. The mixture was slowly added to a cold saturatedNaHCO₃ solution (100 mL) to afford a solid, which was collected byfiltration and washed with water (100 mL), then hexane (100 mL). Thesolid was dried in vacuo to afford1-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-6-fluoro-2-methyl-1H-benzimidazole(1.25 g, 85% yield).

Step 7. Dioxane (2 mL) was added to a mixture of1-[6-chloro-2-(methylsulfonyl)pyrimidin-4-yl]-6-fluoro-2-methyl-1H-benzimidazole(120.0 mg, 0.35 mmol), N-(4-methoxyphenyl)formamide (53.2 mg, 0.35 mmol)and NaH (8.5 mg, 0.35 mmol) at 0° C. The mixture was stirred at ambienttemperature for 90 minutes, then partitioned between ethyl acetate andwater. The organic phase was washed with water, then brine, dried overMgSO₄, then filtered and the remaining liquid evaporated. The residueN-[4-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]-N-(4-methoxyphenyl)formamidewas used directly in the next step without purification.

Step 8. A microwave tube (5 mL) was charged withN-[4-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]-N-(4-methoxyphenyl)formamide,DMSO (3 mL) and ammonium hydroxide (28-30%, 0.3 mL). The tube was sealedand placed in a microwave oven and heated at 100° C. for 40 minutes. Themixture was partitioned between ethyl acetate and water, the organicphase was washed twice with water followed by brine, dried over MgSO₄,then filtered and the remaining liquid evaporated. The residual materialwas triturated with dichloromethane-hexane to afford the title compoundas a white solid (102.7 g, 80% yield); m.p. 161-162° C.; ¹H NMR (500MHz, Acetone-d₆) δ 8.20-8.39 (br, s, 1H), 7.70 (d, J=8.51 Hz, 2H), 7.57(dd, J=8.83, 5.04 Hz, 1H), 7.42 (dd, J=9.46, 2.52 Hz, 1H), 6.99-7.07 (m,1H), 6.86 (d, J=8.51 Hz, 2H), 6.45 (br. s., 2H), 6.21 (s, 1H), 3.77 (s,3H), 2.67 (s, 3H). MS (ES+) m/e 365.2 (100), 366.2 (20).

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 14 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 1346-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.35 (br. s., 1H), 7.70 (d, J= 8.20 Hz, 2H), 7.58 (dd, J = 8.67, 4.89 Hz, 1H), 7.43 (dd, J = 9.46,2.52 Hz, 1H), 7.08 (d, J = 8.20 Hz, 2 H), 7.00-7.06 (m, 1H), 6.47 (br.s., 2H), 6.23 (s, 1H), 2.68 (s, 3H), 2.27 (s, 3H); m.p.: 118-120° C.; MSm/z 349.2 [M + H]⁺ 135N²-(4-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.63 (s, 1H), 7.89 (d, J =8.30 Hz, 2H), 7.58 (dd, J = 8.83, 5.04 Hz, 1H), 7.42 (dd, J = 9.62, 2.36Hz, 1H), 7.28 (d, J = 8.30 Hz, 2H), 7.04 (ddd, J = 9.77, 8.83, 2.52 Hz,1H), 6.58 (br. s., 2H), 6.29 (s, 1H), 2.68 (s, 3H); m.p.: 149-151° C.;MS m/z 369.1 [M + H]⁺ 136N²-[4-(dimethylamino)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.11 (br. s.,1H), 7.51-7.68 (m, 3H), 7.41 (dd, J = 9.46, 2.52 Hz, 1H), 6.93-7.10 (m,1H), 6.72 (d, J = 8.51 Hz, 2H), 6.37 (br. s., 2 H), 6.16 (s, 1H), 2.91(s, 6 H), 2.67 (s, 3H); m.p.: 232-235° C.; MS m/z 378.2 [M + H]⁺ 1374-{[4-amino-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile ¹H NMR (500 MHz, Acetone-d₆) δ 8.95-9.30 (m, 1H),8.09 (dd, J = 8.99, 7.41 Hz, 2 H), 7.66 (dd, J = 14.50, 8.83 Hz, 2H),7.58 (d, J = 4.73 Hz, 1H), 7.40-7.51 (m, 1H), 6.99-7.09 (m, 1H), 6.71(br. s, 1H), 6.47 (br. s, 1H), 6.37 (d, J = 4.10 Hz, 1H), 2.83 (s, 3H);m.p.: 183-185° C.; MS m/z 360.2 [M + H]⁺ 1386-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-fluorophenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.72 (s, 1H), 7.98 (d, J =12.61 Hz, 1H), 7.58 (dd, J = 8.83, 5.04 Hz, 1H), 7.47-7.51 (m, 1H), 7.44(dd, J = 9.46, 2.52 Hz, 1H), 7.24- 7.30 (m, 1H), 7.01-7.08 (m, 1H), 6.70(dd, J = 2.52, 0.63 Hz, 1H), 6.66 (br. s., 2 H), 6.31 (s, 1H), 2.69 (s,3H); m.p.: 239-241° C.; MS m/z 353.1 [M + H]⁺ 1396-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.35 (s, 1H), 7.69 (s, 1H),7.63 (d, J = 8.20 Hz, 1 H), 7.58 (dd, J = 8.83, 5.04 Hz, 1H), 7.45 (dd,J = 9.46, 2.52 Hz, 1H), 7.14 (t, J = 7.88 Hz, 1H), 6.99-7.08 (m, 1H),6.75-6.84 (m, 1H), 6.49 (br. s., 2H), 6.25 (s, 1 H), 2.69 (s, 3H), 2.28(s, 3H); m.p.: 156-158° C.; MS m/z 349.1 [M + H]⁺ 1406-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 7.79 (d, J = 7.88 Hz, 1H),7.62 (br. s., 1H), 7.55 (dd, J = 8.67, 4.89 Hz, 1H), 7.39 (dd, J = 9.46,2.21 Hz, 1H), 7.21 (d, J = 7.57 Hz, 1 H), 7.17 (t, J = 7.57 Hz, 1H),6.97-7.07 (m, 2H), 6.41 (br. s., 2H), 6.22 (s, 1H), 2.63 (s, 3H), 2.33(s, 3H); m.p.: 127-129° C.; MS m/z 365.2 [M + H]⁺; MS (ES+) m/e (100),366.2 (20) 141N²-(3-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.67 (s, 1H), 8.13 (t, J =2.05 Hz, 1H), 7.70 (ddd, J = 8.28, 1.97, 0.79 Hz, 1H), 7.58 (dd, J =8.83, 5.04 Hz, 1H), 7.44 (dd, J = 9.46, 2.52 Hz, 1H), 7.27 (t, J = 8.04Hz, 1H), 7.01-7.10 (m, 1H), 6.92-7.00 (m, 1H), 6.63 (br. s., 2H), 6.31(s, 1H), 2.69 (s, 3H); m.p.: 211-213° C.; MS m/z 369.2 [M + H]⁺ 142N²-(3-fluoro-4-methoxyphenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.43-8.57 (s,1H), 7.83-7.99 (m, 1H), 7.58 (dd, J = 8.67, 4.89 Hz, 1H), 7.43 (dd, J =9.46, 2.21 Hz, 2H), 6.98-7.11 (m, 2H), 6.58 (br. s., 2H), 6.26 (s, 1H),3.85 (s, 3H), 2.68 (s, 3H); m.p.: 166-167° C.; MS m/z 383.2 [M + H]⁺ 1436-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-phenylpyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.46 (s, 1H), 7.84 (dd, J =8.67, 1.10 Hz, 2H), 7.57 (dd, J = 8.83, 5.04 Hz, 1H), 7.43 (dd, J =9.46, 2.52 Hz, 1H), 7.26 (dd, J = 8.51, 7.57 Hz, 2H), 7.03 (ddd, J =9.77, 8.83, 2.52 Hz, 1H), 6.91-6.99 (m, 1H), 6.52 (br. s., 2H), 6.25 (s,1H), 2.68 (s, 3H); m.p.: 158-161° C.; MS m/z 335.1 [M + H]⁺ 158N²-(4-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.38 (s, 1H), 7.71 (d, J =8.20 Hz, 2H), 7.61 (dd, J = 5.04, 8.83 Hz, 1H), 7.38 (dd, J = 2.21, 9.46Hz, 1H), 7.08 (d, J = 8.20 Hz, 2H), 7.04 (ddd, J = 2.68, 8.75, 9.69 Hz,1H), 6.52 (br. s., 2H), 6.20-6.25 (s, 1H), 2.27 (s, 3H); m.p.: 185-187°C.; MS m/z 385.2 [M + H]⁺ 1596-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-phenylpyrimidine-2,4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.47 (br. s., 1H), 7.84 (dd, J= 0.95, 8.51 Hz, 2H), 7.60 (dd, J = 4.89, 8.67 Hz, 1H), 7.37 (dd, J =2.52, 9.46 Hz, 1H), 7.22-7.29 (m, 2H), 7.03 (ddd, J = 2.52, 8.83, 9.77Hz, 1H), 6.92-6.98 (m, 1H), 6.56 (br. s., 2H), 6.24 (s, 1H), 3.08 (q, J= 7.57 Hz, 2H), 2.05 (td, J = 2.21, 4.41 Hz, 3H); m.p.: 160-162° C.; MSm/z 350.2 [M + H]⁺ 1606-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.37 (s, 1H), 7.71 (d, J =8.20 Hz, 2H), 7.60 (dd, J = 4.89, 8.67 Hz, 1H), 7.37 (dd, J = 2.52, 9.46Hz, 1H), 7.08 (d, J = 8.20 Hz, 2H), 6.99- 7.05 (m, 1H), 6.51 (br. s.,2H), 6.19-6.25 (m, 1H), 3.09 (q, J = 7.57 Hz, 2H), 2.27 (s, 3H),1.29-1.40 (m, 3H); m.p.: 187-189° C.; MS m/z 364.2 [M + H]⁺ 1616-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.29 (br. s., 1H), 7.71 (d, J= 9.14 Hz, 2H), 7.61 (dd, J = 4.89, 8.67 Hz, 1H), 7.38 (dd, J = 2.36,9.30 Hz, 1H), 7.05 (dd, J = 0.95, 2.52 Hz, 1H), 6.82-6.93 (d, J = 9.14Hz, 2H), 6.47 (br. s., 2H), 6.21 (s, 1H), 3.78 (s, 3H), 3.09 (q, J =7.46 Hz, 2H), 1.30-1.41 (m, 3H); m.p.: 166-168° C.; MS m/z 380.2 [M +H]⁺ 162N²-[4-(dimethylamino)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.12 (br. s., 1H), 7.51-7.68(m, 4H), 7.36 (dd, J = 2.52, 9.46 Hz, 1H), 6.94-7.09 (m, 1H), 6.71 (d, J= 8.51 Hz, 2H), 6.40 (br. s., 1H), 6.15 (s, 1H), 3.07 (q, J = 7.46 Hz,2H), 2.77-2.96 (m, 6H), 1.32 (t, J = 7.57 Hz, 3H); m.p.: 230-232° C.; MSm/z 392.3 [M + H]⁺ 1636-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-fluorophenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.73 (br. s., 1H), 7.98 (d, J= 12.61 Hz, 1H), 7.61 (dd, J = 4.89, 8.67 Hz, 1H), 7.48 (d, J = 7.88 Hz,1H), 7.39 (dd, J = 2.52, 9.46 Hz, 1H), 7.20-7.32 (m, 1H), 6.97-7.11 (m,1H), 6.63-6.79 (m, 3H), 6.29 (s, 1H), 3.09 (q, J = 7.57 Hz, 2H),1.30-1.41 (m, 3H); m.p.: 169-171° C.; MS m/z 367.0 [M + H]⁺ 164N²-(3-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.69 (s, 1H), 8.06-8.17 (m,1H), 7.66-7.72 (m, 1H), 7.61 (dd, J = 5.04, 8.83 Hz, 1H), 7.39 (dd, J =2.36, 9.30 Hz, 1H), 7.26 (t, J = 8.04 Hz, 1H), 7.04 (ddd, J = 2.52,8.67, 9.62 Hz, 1H), 6.97 (ddd, J = 0.79, 2.05, 7.88 Hz, 1H), 6.68 (br.s., 2H), 6.30 (s, 1H), 3.02-3.22 (m, 2H), 1.33-1.37 (m, 3H); m.p.:170-172° C.; MS m/z 383.0 [M + H]⁺ 1656-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.47 (s, 1H), 7.55-7.68 (m,2H), 7.39 (dd, J = 2.52, 9.46 Hz, 1H), 7.30-7.35 (m, 1H), 7.15 (t, J =8.20 Hz, 1H), 7.04 (ddd, J = 2.52, 8.83, 9.77 Hz, 1H), 6.59 (br. s.,2H), 6.51-6.56 (m, 1H), 6.25 (s, 1H), 3.74 (s, 3H), 3.09 (q, J = 7.36Hz, 2H), 1.25-1.40 (t, J = 7.40 Hz, 3H); m.p.: 133-135° C.; MS m/z 379.0[M + H]⁺ 1666-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.38 (s, 1H), 7.68 (s, 1H),7.56-7.66 (m, 2H), 7.40 (dd, J = 2.52, 9.46 Hz, 1H), 7.14 (t, J = 7.88Hz, 1H), 7.00-7.09 (m, 1H), 6.78 (d, J = 7.57 Hz, 1H), 6.54 (br. s.,2H), 6.24 (s, 1H), 3.10 (q, J = 7.57 Hz, 2H), 2.28 (s, 3H), 1.35 (t, J =7.41 Hz, 3H); m.p.: 149-150° C.; MS m/z 363.0 [M + H]⁺ 1674-{[4-amino-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile ¹H NMR (500 MHz, Acetone-d₆) δ 9.01 (br. s., 1H),8.09 (d, J = 8.51 Hz, 2H), 7.53- 7.76 (m, 3H), 7.30-7.44 (m, 1H), 7.05(t, J = 8.04 Hz, 1H), 6.75 (br. s., 2H), 6.36 (s, 1H), 3.09 (q, J = 7.25Hz, 2H), 1.25-1.47 (m, 3H); m.p.: 252-255° C.; MS m/z 375.2 [M + H]⁺ 1686-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-fluoro-4-methoxyphenyl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ8.48 (br. s., 1H), 7.86-8.00 (m, 1H), 7.60 (dd, J = 4.89, 8.67 Hz, 1H),7.38 (dt, J = 2.05, 10.01 Hz, 2H), 6.95-7.11 (m, 2H), 6.60 (br. s., 2H),6.24 (s, 1H), 3.84 (s, 3H), 3.08 (q, J = 7.46 Hz, 2H), 1.35 (t, J = 7.41Hz, 3H); m.p.: 129-131° C.; MS m/z 397.0 [M + H]⁺ 174N²-(4-chloro-3-fluorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.57-8.73 (m,1H), 8.04 (dd, J = 5.04, 8.83 Hz, 1H), 7.94-7.99 (m, 1H), 7.89 (dd, J =2.52, 9.46 Hz, 1H), 7.82 (t, J = 8.67 Hz, 1H), 7.47-7.53 (m, 1H), 7.18(br. s., 2H), 6.78 (s, 1H), 3.14 (s, 3H); m.p.: 258- 260° C.; MS m/z389.2 [M + H]⁺ 175N²-(4-chloro-3-fluorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ 8.83 (s, 1H), 8.20 (dd, J =2.36, 12.77 Hz, 1H), 7.62 (dd, J = 4.89, 8.67 Hz, 1H), 7.52 (td, J =1.22, 8.91 Hz, 1H), 7.33-7.42 (m, 2H), 7.05 (ddd, J = 2.52, 8.67, 9.62Hz, 1H), 6.74 (br. s., 2H), 6.32 (s, 1H), 3.09 (q, J = 7.36 Hz, 2H),2.06 (td, J = 2.21, 4.41 Hz, 3H); m.p.: 209-211° C.; MS m/z 401.2 [M +H]⁺

Example 156-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 1)

Step 1. 4-Fluoropyridin-2-amine (8.57 g, 76.44 mmol) and chloroacetone(12.99 g, 71.67 mmol) was pre-mixed and stirred in a 250 mL round bottomflask at 0° C. for 15 min. The resulting mixture was diluted withacetonitrile (80 mL) and stirred at reflux overnight. The acetonitrilewas evaporated, ethyl ether (200 mL) was added to afford a precipitatewhich was collected by filtration. The solid was partitioned betweendichloromethane (300 mL) and NaHCO₃ (250 mL). The organic layer wasseparated, dried over MgSO₄, then filtered and the remaining liquidevaporated. The residual material was separated by silica gel columnchromatography (1:1 ethyl acetate-hexane) to afford6-fluoro-2-methylimidazo[1,2-a]pyridine (5.20 g, 46% yield) as a glassysolid. ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.95-7.99 (m, 1H), 7.46 (dd,J=5.04, 9.77 Hz, 1H), 7.34 (s, 1H), 6.99-7.06 (m, 1H), 2.44 (d, J=0.63Hz, 3H). MS (ES+) m/e 151.0 (100)

Step 2. A mixture of 6-fluoro-2-methylimidazo[1,2-a]pyridine (445.0 mg,2.97 mmol), di-tert-butyl(6-chloro-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)imidodicarbonate(1.0 g, 5.78 mmol), palladium (II) acetate (33.4 mg, 0.149 mmol),triphenylphosphane (46.7 mg, 0.178 mmol), cesium acetate (1.14 g, 5.94mmol) and DMA (5 mL) was degassed by three cycles of vacuum pumping andN₂ purging. The mixture was heated to 100° C. for one hour, then cooledand poured into water (50 mL) and extracted with dichloromethane. Theextract was dried over MgSO₄, filtered and the remaining liquidevaporated. The residue was triturated with ethyl ether to afforddi-tert-butyl[6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]imidodicarbonate(706.0 mg, 83% yield)

Step 3. A solution of di-tert-butyl[6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]imidodicarbonate(140 mg, 0.24 mmol) in dichloromethane (2 mL) was treated with TFA (0.4mL) at 0° C. The resulting mixture was stirred at ambient temperaturefor 4 hours. The solvent was evaporated and the residual materialtriturated with ethyl ether to afford the title compound as a whitesolid (87.0 mg, 87% yield). m.p. 216-218° C. ¹H NMR (500 MHz, DMSO-d₆) δ9.77 (dd, J=2.21, 5.67 Hz, 1H), 9.58 (s, 1H), 8.00 (d, J=8.51 Hz, 2H),7.64 (dd, J=5.52, 9.62 Hz, 1H), 7.57 (d, J=8.51 Hz, 2H), 7.38-7.49 (m,1H), 6.86 (br. s., 2H), 6.32 (s, 1H), 2.60 (s, 3H). MS (ES+) m/e 403.4(100), 404.4 (30), 405.5 (10).

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 15 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 2N²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3- yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, Acetone-d₆) δ9.91 (br. s, 1H), 9.48-9.67 (m, 1H), 7.91-8.01 (m, 1H), 7.82 (dd, J =8.83 Hz, 2H), 7.61-7.68 (m, 1H), 7.15 (d, J = 8.83 Hz, 2H), 6.77-7.06(t, J = 72.50 Hz, 1H), 6.52 (s, 1H), 2.68 (s, 3H); m.p.: 189-190° C.; MSm/z 401.5 [M + H]⁺ 9 6-(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)-3- fluorophenyl]pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.72-9.85 (m, 1H), 9.63 (s, 1H),8.25-8.38 (m, 1H), 7.74-7.84 (m, 1H), 7.58-7.68 (m, 2H), 7.36-7.50 (m,1H), 7.16-7.44 (t, J = 70.00 Hz, 1H), 7.05 (br. s, 1H), 6.71 (s, 1H),2.43-2.57 (m, 1H), 1.25 (m, 4H); m.p.: 189-190° C.; MS m/z 445.5 [M +H]⁺ 63 6-[2-(difluoromethyl)-6-fluoroimidazo[1, 2-a]pyridin-3-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,DMSO-d₆) δ 10.79 (s, 1H), 10.10 (s, 1H), 9.57-9.63 (m, 1H), 8.09 (d, J =8.51 Hz, 2H), 7.97 (s, 1H), 7.89-7.95 (m, 1H), 7.67-7.72 (m, 1H), 7.65(d, J = 8.83 Hz, 1H), 7.22-7.43 (t, J = 52.50 Hz, 1H); m.p.: 242-245°C.; MS m/z 439.4 [M + H]⁺

Example 166-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine(Cpd 170)

Step 1. A mixture of 6-fluoro-2-methylimidazo[1,2-a]pyridine (5.0 g,33.33 mmol), N-iodosuccinimide (5.28 g, 33.33 mmol) and chloroform (60mL) was stirred at ambient temperature for 3 hours. The mixture waspartitioned between dichloromethane (250 mL) and a saturated NaHCO₃solution (150 mL). The organic phase was washed with brine, dried overMgSO₄, then filtered and the remaining liquid evaporated. The residualmaterial was washed with hexane to afford6-fluoro-3-iodo-2-methylimidazo[1,2-a]pyridine (7.63 g, 83% yield). MS(ES+) ink 277.4 (80), 278.0 (100).

Step 2. To a solution of 6-fluoro-3-iodo-2-methylimidazo[1,2-a]pyridine(3.56 g, 12.90 mmol) in THF (25 mL) was added an isopropylmagnesiumchloride lithium chloride complex solution (12.0 mL, 1.3 M in THF) at−78° C. dropwise. After the addition, the mixture was warmed to 0° C.and stirred at 0° C. for 30 minutes. In one portion,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.12 g, 16.8 mmol)was added at −78° C., then the mixture was stirred at 0° C. for 2 hours.

Step 3. A mixture of 4,6-dichloro-2-(methylthio)pyrimidine (5.03 g, 25.8mmol), Pd₂dba₃ (916.0 mg, 0.645 mmol), tricyclohexylphosphine (361.2 mg,1.3 mmol), tribasic potassium phosphate (5.50 g, 25.80 mmol), dioxane(25 mL) and water (3.0 mL) under nitrogen was degassed by three cyclesof vacuum pumping and N₂ purging and then heated to 80° C. for 3 hours.The solution was cooled and poured into water (20 mL), then the mixturewas extracted with ethyl acetate. The extract was dried over MgSO₄,filtered and the remaining liquid evaporated. The residual material wasseparated by silica gel column chromatography, eluting with 1:4 ethylacetate:dichloromethane to afford3-(6-chloro-2-(methylthio)pyrimidin-4-yl)-6-fluoro-2-methylimidazo[1,2-a]pyridine(773.0 mg, 20% yield).

Step 4. To a suspension of3-(6-chloro-2-(methylthio)pyrimidin-4-yl)-6-fluoro-2-methylimidazo[1,2-a]pyridine(515.0 mg, 1.67 mmol) in DCM (5 mL), meta-chloroperoxybenzoic acid (1.24g, 7.19 mmol) was added in portions at 0° C. The resulting mixture wasstirred at ambient temperature for one hour, then partitioned betweenDCM and saturated NaHCO₃. The organic phase was washed with brine, driedover MgSO₄, then filtered and the remaining liquid evaporated to afford3-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-6-fluoro-2-methylimidazo[1,2-a]pyridine(567.0 mg, 71% yield).

Step 5. Using3-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-6-fluoro-2-methylimidazo[1,2-a]pyridine,the title compound was prepared using the procedure described in Example26, Step 1 and 2; m.p. 197-199° C. ¹H NMR (500 MHz, Acetone-d₆) δ9.74-9.82 (m, 1H), 8.20 (s, 1H), 7.65 (d, J=8.51 Hz, 2H), 7.52 (dd,J=5.36, 9.77 Hz, 1H), 7.24-7.31 (m, 1H), 6.84-6.89 (d, J=8.51 Hz, 2H),6.34 (s, 1H), 6.13 (br. s, 2H), 3.77 (s, 3H), 2.59 (s, 3H). MS (ES+) m/e365.2 (100).

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 16 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 169 6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(4-fluorophenyl)pyrimidine-2, 4- diamine ¹H NMR(500 MHz, Acetone-d₆) δ 9.79 (dd, J = 2.21, 5.67 Hz, 1H), 8.84 (s, 1H),7.76- 7.91 (m, 2H), 7.55 (dd, J = 5.36, 9.77 Hz, 1H), 7.26-7.38 (m, 1H),6.96-7.08 (m, 2H), 6.46 (br. s., 2H), 6.37 (s, 1H), 2.61 (s, 3H); m.p.:250-253° C.; MS m/z 355.2 [M + H]⁺ 171 6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(4-methylphenyl)pyrimidine-2, 4- diamine ¹H NMR(500 MHz, Acetone-d₆) δ 9.80 (d, J = 3.47 Hz, 1H), 8.21-8.46 (m, 1H),7.67 (dd, J = 1.00, 8.83 Hz, 2H), 7.50-7.58 (m, 1H), 7.25-7.33 (m, 1H),7.09 (d, J = 8.51 Hz, 2H), 6.37 (s, 1H), 6.19 (br. s., 2H), 2.61 (s,3H), 2.28 (s, 3H); m.p.: 217- 220° C.; MS m/z 350.2 [M + H]⁺ 172N²-(4-chlorophenyl)-6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2, 4- diamine ¹H NMR (500 MHz, Acetone-d₆) δ9.78 (dd, J = 2.21, 5.67 Hz, 1H), 8.82 (s, 1H), 7.88 (d, J = 8.83 Hz,2H), 7.55 (dd, J = 5.36, 9.77 Hz, 1H), 7.29-7.36 (m, 1H), 7.23-7.27 (d,J = 8.83 Hz, 2H), 6.43 (s, 1H), 6.41 (s, 2H), 2.62 (s, 3H); m.p.:243-246° C.; MS m/z 371.1 [M + H]⁺ 173 6-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N²-(3-methylphenyl)pyrimidine-2, 4- diamine ¹H NMR(500 MHz, Acetone-d₆) δ 9.83 (dd, J = 2.36, 5.83 Hz, 1H), 8.58 (br. s.,1H), 7.70 (s, 1H), 7.52-7.64 (m, 2H), 7.28-7.37 (m, 1H), 7.14 (t, J =7.72 Hz, 1H), 6.76 (d, J = 7.57 Hz, 1H), 6.38 (s, 1H), 6.37 (br. s.,2H), 2.62 (s, 3H), 2.29 (s, 3H); m.p.: 250-252° C.; MS m/z 350.2 [M +H]⁺

Example 176-(2-cyclopropyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 107)

Step 1. A mixture of 2-chloro-4-fluoropyridine (7.13 g, 54.20 mmol),ethynylcyclopropane (10.2 g, 81.31 mmol),bis(acetonitrile)dichloropalladium(II) (352.4 mg, 1.35 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (649.0 mg, 1.36mmol) in NMP (40 mL) was degassed by three cycles of vacuum pumping andN₂ purging, then triethylamine (15.3 mL, 107.7 mmol) was added. Themixture was degassed and purged with N₂, then heated to 60° C. forovernight. The solution was cooled and poured into water, and themixture was extracted with ethyl acetate. The extract was dried overMgSO₄, filtered and the remaining liquid evaporated. The residualmaterial was separated by column chromatography, eluting with 0:10%dichloromethane:hexane to afford 2-(cyclopropylethynyl)-4-fluoropyridineas an oil (6.0 g, 69% yield).

Step 2. To a solution of 2-(cyclopropylethynyl)-4-fluoropyridine (291.0mg, 1.81 mmol) in dichloromethane (3.0 mL) was added2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (584.0 mg, 2.72 mmol)portionwise at 0° C. The resulting mixture was stirred at ambienttemperature for 2 days. The solvent was removed using an N₂ stream togive a crude mixture

Step 3. To the crude mixture in DMF (3 mL) was added K₂CO₃ (500.1 mg,3.62 mmol) at 0° C. The resulting mixture was stirred at ambienttemperature for 24 hours then partitioned between ethyl acetate andwater. The organic phase was washed with water and brine, dried overMgSO₄, then filtered and the remaining liquid evaporated. The residualmaterial was separated by column chromatography, eluting with 0:10%ethyl acetate:dichloromethane to afford2-cyclopropyl-5-fluoropyrazolo[1,5-a]pyridine as an oil (204.1 mg, 64%yield).

Step 4. A mixture of 2-cyclopropyl-5-fluoropyrazolo[1,5-a]pyridine(194.0 mg, 1.10 mmol), N-iodosuccinimide (247.7 mg, 1.10 mmol) inchloroform (2 mL) was stirred at ambient temperature for 1 h. Themixture was partitioned between ethyl acetate and water. The organicphase was washed with water and brine, dried over MgSO₄, then filteredand the remaining liquid evaporated. The residual material was separatedby silica gel column chromatography, eluting with 1:1dichloromethane:hexane, then 1% methanol in 1:4 ethylacetate:dichloromethane to afford2-cyclopropyl-5-fluoro-3-iodopyrazolo[1,5-a]pyridine (329.0 mg, 98%yield).

Step 5. Using the procedure described in Example 10, Step 3,2-cyclopropyl-5-fluoro-3-iodopyrazolo[1,5-a]pyridine,2-cyclopropyl-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridinewas prepared (95.0 mg, 37% yield).

Step 6. Using the procedure described in Example 10, Step 4, the titlecompound was prepared; m.p. 130-132° C. ¹H NMR (500 MHz, Acetone-d₆) δ8.75 (s, 1H), 8.45-8.58 (m, 1H), 8.04-8.20 (m, 3H), 7.57 (d, J=8.51 Hz,2H), 6.85 (dt, J=3.00, 7.33 Hz, 1H), 6.77 (s, 1H), 6.19 (br. s., 2H),2.38-2.46 (m, 1H), 1.04-1.11 (m, 4H).

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 17 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 106 6-(2-cyclopropyl-5-methoxypyrazolo[1,5-a]pyridin-3-yl)-N²-[4- (trifluoromethyl)phenyl]pyrimidine-2, 4-diamine¹H NMR (500 MHz, Acetone-d₆) δ 8.74 (br. s, 1H), 8.31 (d, J = 7.57 Hz,1H), 8.12 (d, J = 8.83 Hz, 2H), 7.47-7.73 (m, 3H), 6.47-6.77 (m, 2H),6.18 (br. s., 2H), 3.79 (s, 3H), 2.34-2.47 (m, 1H), 0.96-1.18 (m, 4H);m.p.: 172-174° C. 111 6-(2-ethyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N²-[4- (trifluoromethyl)phenyl]pyrimidine-2, 4-diamine¹H NMR (500 MHz, Acetone-d₆) δ 8.72 (s, 1H), 8.51-8.63 (m, 1H), 8.13(dd, J = 2.68, 10.25 Hz, 1H), 8.08 (d, J = 8.51 Hz, 2H), 7.56 (d, J =8.51 Hz, 2H), 6.86 (dt, J = 2.84, 7.41 Hz, 1H), 6.44 (s, 1H), 6.18 (br.s., 2H), 3.08 (q, J = 7.57 Hz, 2H), 1.35 (t, J = 7.57 Hz, 3H); m.p.:153-157° C. 1173-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-2, 5, 6-trimethylpyrazolo[1, 5-c]pyrimidin-7(6H)-one m.p.: 270-273° C.; MS m/z430.3 [M + H]⁺ 126 6-(2-cyclopropylpyrazolo[1, 5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,Acetone-d₆) δ 8.64 (s, 1H), 8.48 (dd, J = 0.95, 6.94 Hz, 1H), 8.28- 8.41(m, 1H), 8.15 (d, J = 8.51 Hz, 2H), 7.57 (d, J = 8.51 Hz, 2H), 7.29(ddd, J = 1.26, 6.78, 8.99 Hz, 1H), 6.91 (dt, J = 1.26, 6.78 Hz, 1H),6.72 (s, 1H), 6.15 (br. s., 2H), 2.37-2.58 (m, 1H), 1.00-1.19 (m, 4H);m.p.: 181-183 ° C.

Example 186-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 34)

Step 1. To 5,7-difluoro-2-methyl-1H-benzo[d]imidazole (600 mg, 3.57mmol) was added 4,6-dichloro-2-(methylthio)pyrimidine (1.4 g, 7 mmol),Cs₂CO₃, (1.3 g, 4 mmol) and acetonitrile (20 mL). The mixture wasstirred at 80° C. for 25 minutes, cooled and diluted withdichloromethane, then filtered, concentrated and purified bychromatography on silica gel (gradient using ethyl acetate:hexane from1:10 to 1:2) to provide1-(6-chloro-2-(methylthio)pyrimidin-4-yl)-4,6-difluoro-2-methyl-1H-benzo[d]imidazole(0.70 g, 60%) as an off-white solid.

Step 2. To1-(6-chloro-2-(methylthio)pyrimidin-4-yl)-4,6-difluoro-2-methyl-1H-benzo[d]imidazolewas added dichloromethane (10 mL), acetonitrile (10 mL), water (10 mL)and KMnO₄ (0.47 g, 3 mmol), followed by an aqueous solution of sulfuricacid (1 mL, 4N). The reaction mixture was stirred at room temperaturefor 10 minutes, decolorized with NaHSO₃, then neutralized with excess ofKOAc and extracted with dichloromethane. The product was concentrated invacuo to provide1-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-4,6-difluoro-2-methyl-1H-benzo[d]imidazoleas an off-white solid (818 mg, 107%).

Step 3. To1-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-4,6-difluoro-2-methyl-1H-benzo[d]imidazolewas added 4-(trifluoromethyl)aniline (640 mg, 4 mmol), DMF (2 mL) andTHF (6 mL). The reaction mixture was cooled to −60° C., then a solutionof KOt-Bu (1M) in THF (5 mL, 5 mmol) was added. After one hour at −60°C., the reaction was quenched with AcOH, then the solution was dilutedwith water and filtered to provide crude4-chloro-6-(4,6-difluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine.

Step 4. The crude material was heated in a sealed tube with DMSO (2 mL),acetonitrile (10 mL), and NH₄OH (3 mL) at 110° C. (heating blocktemperature) for 17 hours. The reaction mixture was diluted with water,then filtered and purified by chromatography on silica gel (gradientusing ethyl acetate:hexane from 1:2 to ethyl acetate:methanol 10:1) toprovide the title compound over four steps as a white solid (0.59 g,39%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.00 (d(AB), J=8.8 Hz,2H), 7.59 (d(AB), J=8.5 Hz, 2H), 7.35 (dd, J=8.8, 2.2 Hz, 1H), 7.21 (br.s., 2H), 7.17 (td, J=10.4, 2.2 Hz, 1H), 6.20 (s, 1H), 2.67 (s, 3H); MS(ESI) M+1=421.

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 18 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 49 N²-[4-(difluoromethoxy)phenyl]-6-(5,7-difluoro-2-methyl-1H-benzimidazol-1- yl)pyrimidine-2, 4-diamine ¹H NMR(500 MHz, DMSO-d₆) δ 9.39 (s, 1H), 7.76 (d, J = 9.1 Hz, 2H), 7.34 (dd, J= 9.1, 2.2 Hz, 1H), 6.91-7.24 (m, 6H), 6.07 (d, J = 1.9 Hz, 1H), 2.53(s, 3H); MS m/z 419 [M + H]⁺ 51N²-[4-(difluoromethoxy)phenyl]-6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2, 4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 9.40 (s, 1H),7.79 (d, J = 9.1 Hz, 2H), 7.41 (d(AB), J = 7.9 Hz, 1H), 7.24 (td, J =8.2, 5.0 Hz, 1H), 7.04-7.13 (m, 5H), 7.11 (t, J = 74.7 Hz, 1H), 6.12 (s,1H), 2.67 (s, 3H); MS m/z 401 [M + H]⁺ 526-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,DMSO-d₆) δ 9.65 (s, 1H), 7.89 (br. s, 1H), 7.76 (d, J = 8.5 Hz, 1H),7.50 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.24 (td, J = 8.1,4.9 Hz, 1H), 7.19 (br. s., 2H), 7.08 (dd, J = 10.7, 8.2 Hz, 1H), 6.19(s, 1H), 2.68 (s, 3H), 2.36 (s, 3H); MS m/z 417 [M + H]⁺ 53 6-(2,6-dimethyl-1H-benzimidazol-1-yl)-N²-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2, 4-diamine ¹H NMR (500 MHz,DMSO-d₆) δ 9.63 (s, 1H), 7.91 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.50(d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.15 (br.s., 2H), 7.08 (dd, J = 8.2, 0.9 Hz, 1H), 6.18 (s, 1H), 2.65 (s, 3H),2.41 (s, 3H), 2.37 (s, 3H); MS m/z 412 [M + H]⁺ 54N²-[4-(difluoromethoxy)phenyl]-6-(2,6-dimethyl-1H-benzimidazol-1-yl)pyrimidine- 2, 4-diamine ¹H NMR (500MHz, DMSO-d₆) δ 9.35 (s, 1H), 7.80 (d, J = 9.1 Hz, 2H), 7.48 (d, J = 8.2Hz, 1H), 7.38 (s, 1H), 6.99-7.09 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 7.11(t, J = 74.7 Hz, 1H), 6.09 (s, 1H), 2.62 (s, 3H), 2.40 (s, 3H); MS m/z397 [M + H]⁺ 60 N²-[4-(difluoromethoxy)phenyl]-6-(4,6-difluoro-2-methyl-1H-benzimidazol-1- yl)pyrimidine-2, 4-diamine ¹H NMR(500 MHz, DMSO-d₆) δ 9.38 (s, 1H), 7.75-7.82 (m, 2H), 7.28-7.34 (m, 1H),7.14 (td, J = 10.4, 2.2 Hz, 1H), 7.08 (br. s., 2H), 7.07 (d, J = 9.1 Hz,2H), 7.10 (t, J = 74.7 Hz, 1H), 6.11 (s, 1H), 2.65 (s, 3H); MS m/z 419[M + H]⁺

Example 196-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 35)

Step 1. To di-tert-butyl(6-chloro-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)imidodicarbonate(104 mg, 0.21 mmol) was added 3-fluorobenzene-1,2-diamine (50 mg, 0.4mmol), XPhos (6 mg, 6%), Pd₂dba₃ (6 mg, 3%), K₃PO₄ (90 mg, 2 equiv) andDME (1 mL). The mixture was heated at 100° C. for one hour and cooled,then AcOH (1 mL) and triethyl orthoacetate (1 mL) were added. Thereaction mixture was kept at room temperature for 14 hours, thenpartitioned between water and ethyl acetate. The organic layer was driedand purified using chromatography on silica gel (gradient using ethylacetate:hexane from 1:10 to 1:4) to provide di-tert-butyl(6-[(2-amino-3-fluorophenyl)amino]-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)imidodicarbonateas a yellow oily material (96 mg).

Step 2. di-tert-butyl(6-[(2-amino-3-fluorophenyl)amino]-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)imidodicarbonatewas dissolved in TFA (1 mL) and kept at room temperature for one hour.The reaction mixture was dissolved in ether and precipitated withhexane, then washed with ether to provide (E)-ethylN-2-(6-(bis(tert-butoxycarbonyl)amino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)-6-fluorophenylacetimidate(mono-TFA salt) as a white solid (46 mg, 39%). ¹H NMR (500 MHz, DMSO-d₆)δ 10.01 (br. s., 1H), 8.98 (br. s., 1H), 7.82 (d(AB), J=7.9 Hz, 2H),7.57 (d(AB), J=8.5 Hz, 2H), 7.31-7.40 (m, 1H), 7.09-7.18 (m, 2H), 5.42(br. s., 1H), 4.20 (q, J=6.9 Hz, 2H), 1.75 (s, 3H), 1.24 (t, J=7.1 Hz,3H); MS (ESI) M+1=449.

Step 3. To (E)-ethylN-2-(6-(bis(tert-butoxycarbonyl)amino)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)-6-fluorophenylacetimidate(mono-TFA salt) (31 mg, 0.055 mmol) was added AcOH (1 mL). The solutionwas heated to 120° C. (heating block temperature) for 5 minutes, dilutedwith aqueous NH₄OH, then filtered and washed with water to provide thetitle compound as an off-white solid (21 mg). ¹H NMR (500 MHz, DMSO-d₆)δ 9.77 (s, 1H), 7.93-8.04 (d(AB), J=8.5 Hz, 2H), 7.55-7.61 (d(AB), J=8.5Hz, 2H), 7.43 (dd, J=8.2, 0.6 Hz, 1H), 7.25 (td, J=8.1, 4.9 Hz, 1H),7.21 (br. s., 2H), 7.09 (dd, J=10.6, 7.7 Hz, 1H), 6.21 (s, 1H), 2.68 (s,3H); MS (ESI) M+1=403.

Example 206-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 41)

Step 1. To 4-bromobenzene-1,2-diamine (1.46 g, 7.8 mmol) was added DMF(12 mL). The solution was cooled to −60° C., then2,4,6-trichloropyrimidine (1.03 mL, 9 mmol) was added, followed byNaOt-Am (2.5 M solution in THF, 6.9 mL, 2.2 equiv). After one hour at−60° C., AcOH was added (5 mL), then trimethyl orthoacetate (5 mL) andthe reaction mixture was heated to 60° C. for one hour. The mixture wasthen partitioned between water and dichloromethane, the organic layerwas purified by chromatography on silica gel (gradient using ethylacetate:hexane:dichloromethane from 1:20:1 to 1:4:1), then washed withether to provide6-bromo-1-(2,6-dichloropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(the more polar isomer by both TLC and RP-UPLC) as a brown solid (770mg, 28%). The structure was confirmed by NOESY NMR analysis. ¹H NMR (500MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.63 (d, J=8.5 Hz,1H), 7.49 (dd, J=8.5, 1.9 Hz, 1H), 2.73 (s, 3H).

Step 2. To6-bromo-1-(2,6-dichloropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(235 mg, 0.65 mmol) was added 4-(trifluoromethyl)aniline (161 mg, 1mmol) and DMF (1 mL). The reaction mixture was cooled to −60° C. andNaOt-Am was added (2.5 M solution in THF, 6 mL, 2.2 equiv). After 20min, the reaction mixture was quenched with AcOH, diluted with water,then the solid precipitate was filtered and purified by chromatographyon silica gel (gradient using ethyl acetate:hexane from 1:4 to 1:0).

The less polar isomer was washed with ether to provide4-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-6-chloro-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(52 mg) as an off-white solid material. ¹H NMR (500 MHz, DMSO-d₆) δ10.77 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.70 (d,J=8.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.47-7.48 (m, 1H), 7.46 (dd,J=8.5, 1.9 Hz, 1H), 2.73 (s, 3H).

The structure of the more polar isomer was established by NOESY NMRanalysis as6-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-2-chloro-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine(160 mg of light yellow solid material). ¹H NMR (500 MHz, DMSO-d₆) δ10.72 (s, 1H), 7.94 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.80 (d,J=8.8 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.5, 1.9 Hz, 1H),7.06 (s, 1H), 2.69 (s, 3H).

Step 3. To4-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-6-chloro-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine(50 mg, 0.1 mmol) was added DMSO (0.5 mL) and NH₄OH (0.5 mL). Thereaction mixture was heated in a sealed tube at 110° C. (heating blocktemperature) for 21 hours, diluted with water, then filtered and washedwith water followed by hexane to provide the title compound (44 mg, 95%)as an off-white solid. MS (ESI) M+1=463.

Example 216-(2,6-dimethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine(Cpd 42)

A mixture of Compound 41 (40 mg, 0.09 mmol), QPhos (6 mg, 0.1 equiv),Pd₂dba₃ (4 mg, 0.05 equiv), THF (3 mL) and Me₂Zn (1 M solution inheptane, 0.5 mL, 0.5 mmol) (with gas evolution) was stirred at roomtemperature for one hour, then at 50° C. for one hour. The mixture wasdiluted with EtOAc, then water (100 drops) and MeOH were added. Themixture was filtered through a short plug of silica gel, thenconcentrated and purified by chromatography on silica gel (gradientusing ethyl acetate:hexane from 1:2 to EtOAc:MeOH 10:1) and washed withether to provide the title compound as a grey solid (18 mg, 50%). ¹H NMR(500 MHz, DMSO-d₆) δ 9.48 (br. s, 1H), 7.78 (d(AB), J=8.8 Hz, 2H), 7.35(d(AB), J=8.8 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 6.91 (br.s, 1H), 6.84 (d, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.41 (s, 3H), 2.18 (s,3H); MS (ESI) M+1=399.

Example 22[6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]phosphoramidicacid (Cpd 99)

Step 1. To6-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N²-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine(164 mg, 0.41 mmol) was added THF (2 mL, cooled to −60° C.), NaHMDS (1 Msolution in THF, 0.9 mL, 0.9 mmol) and dimethyl phosphorochloridate(0.065 mL, 0.6 mmol). The reaction mixture was warmed to −10° C. over 30minutes, then quenched with acetic acid and partitioned between waterand EtOAc. The organic layer was purified by chromatography on silicagel (gradient using ethyl acetate:hexane from 1:1 to EtOAc:MeOH 10:1)and washed with ether to provide dimethyl6-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-ylphosphoramidateas a white solid (138 mg, 66%). ¹H NMR (500 MHz, Acetone-d₆) δ 9.32 (br.s, 1H), 8.44 (br. d, J=9.8 Hz, 1H), 8.18 (d, J=8.5 Hz, 2H), 7.63 (d,J=8.8 Hz, 2H), 7.61 (dd, J=8.5, 4.7 Hz, 1H), 7.56 (dd, J=9.5, 2.5 Hz,1H), 7.08 (ddd, J=8.8, 8.8, 2.5 Hz, 1H), 6.83 (s, 1H), 3.87 (s, 3H),3.84 (s, 3H), 2.74 (s, 3H).

Step 2. Dimethyl6-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-ylphosphoramidatewas suspended in acetonitrile (3 mL) and TMSBr was added (0.36 mL, 2.7mmol) at room temperature. After one hour at room temperature, thereaction mixture was left for 15 hours at 4° C. The reaction mixture wasconcentrated, then sonicated with a water:hexane mixture and filtered toprovide the title compound (110 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 9.95(s, 1H), 9.03 (d, J=9.1 Hz, 1H), 8.16 (d, J=8.2 Hz, 1H), 7.65 (dd,J=8.8, 4.7 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.50 (dd, J=9.5, 2.5 Hz,1H), 7.14 (td, J=9.5, 1.9 Hz, 1H), 6.67 (s, 1H), 2.70 (s, 3H); MS (ESI)M+1=483.

Example 235-chloro-N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine(Cpd 197)

Step 1. To 2-methyl-1H-benzo[d]imidazole (493 mg, 3.7 mmol) was addedK₂CO₃ (515 mg, 3.7 mmol) and ACN (5 mL). The mixture was cooled to −60°C., then 5-chloro-2,4,6-trifluoropyrimidine (1.2 mL, 3 Eq.) was addedand the reaction mixture was warmed to 10° C. with stirring over 3hours.

Purification by chromatography on silica gel provided the major,somewhat unstable, more polar isomer1-(5-chloro-2,6-difluoropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole asa crude oily material (450 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 7.65-7.72(m, 1H), 7.39-7.44 (m, 1H), 7.25-7.33 (m, 2H), 2.56 (s, 3H).

The less polar fractions provided the isomeric1-(5-chloro-4,6-difluoropyrimidin-2-yl)-2-methyl-1H-benzo[d]imidazole asa white solid (23 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.14-8.19 (m, 1H),7.62-7.67 (m, 1H), 7.36 (app. quind, J=7.6, 1.4 Hz, 2H), 2.84 (s, 3H);¹³C NMR (500 MHz, DMSO-d₆) δ 166.3 (dd, J=251.6, 12.7 Hz), 152.2, 151.4(t, J=21.8, Hz), 142.2, 132.7, 124.2, 124.0, 119.0, 114.6, 96.8 (t,J=32.7, Hz), 18.3.

Step 2. To the crude1-(5-chloro-2,6-difluoropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(450 mg) was added ACN (5 mL) followed by NH₄OH (1 mL). After 5 minutesat room temperature, the reaction mixture was concentrated and purifiedby chromatography on silica gel, dissolved in ether and precipitatedwith hexane to provide5-chloro-2-fluoro-6-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-4-amineas a white solid (257 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (br. s.,1H), 8.11 (br. s., 1H), 7.60-7.67 (m, 1H), 7.20-7.32 (m, 3H), 2.49 (s,3H); ¹³C NMR (500 MHz, DMSO-d₆) δ 164.4 (d, J=19.1 Hz), 159.7 (d,J=210.7 Hz), 152.5 (d, J=19.1 Hz), 150.5, 142.2, 134.0, 122.8, 122.6,118.7, 111.0, 106.2 (d, J=8.2 Hz), 14.0.

Step 3. To5-chloro-2-fluoro-6-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-4-amine(241 mg, 0.87 mmol) was added 4-methoxyaniline (369 mg, 3 mmol) and NMP(2 mL). The reaction mixture was heated in a microwave oven at 160° C.for 30 minutes, diluted with water, then the resulting precipitate waspurified by chromatography on silica gel and washed with an ether/EtOAcmixture to provide the title compound as a grey solid (230 mg, 70%). ¹HNMR (500 MHz, DMSO-d₆) δ 9.29 (s, 1H), 7.55-7.65 (m, 3H), 7.4 (br. s,2H), 7.17-7.25 (m, 3H), 6.82 (app. d, J=9.1 Hz, 2H), 3.69 (s, 3H), 2.49(br. s., 3H)

Example 24N²-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)pyrimidine-2,4-diamine(Cpd 198)

Step 1. A solution of 4-amino-6-chloro-2-methylthiopyrimidine (8.64 g,49.2 mmol) and 4-dimethylaminopyridine (636 mg, 5.21 mmol) indichloromethane (60 mL) was treated with di-tert-butyl dicarbonate (23.6g, 108 mmol) in small portions over 30 minutes. The solution was allowedto stir at ambient temperature for 12 hours, was diluted withdichloromethane (150 mL), washed twice with water (200 mL) followed bysaturated brine (100 mL), dried over Na₂SO₄, then filtered and theremaining liquid evaporated. The resulting solid was triturated with 1:1pentane:ether, collected by filtration and dried under vacuum to afford4-bis(tert-butoxycarbonyl)amino-6-chloro-2-methylthiopyrimidine as awaxy off-white solid (12.19 g, 32.4 mmol, 66%); m.p. 90-91° C.; TLCR_(F) 0.30 (10:90 ethyl acetate-hexane). ¹H NMR (500 MHz, CDCl₃) δ 7.48(1H, s), 2.49 (3H, s), 1.55 (18H, s).

Step 2. A mixture of4-bis(tert-butoxycarbonyl)amino-6-chloro-2-methylthiopyrimidine (1.581g, 4.21 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (939mg, 4.21 mmol), 1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)-dichloromethane complex (217 mg, 0.266 mmol) andaqueous sodium carbonate solution (4.2 mL, 2.0 N, 8.4 mmol) in dioxane(20 mL) was degassed by three cycles of vacuum pumping and N₂ purging.The mixture was heated to reflux for 12 hours, then cooled andpartitioned between water and dichloromethane (100 mL each). The organiclayer was separated, dried over MgSO₄, then filtered and the remainingliquid evaporated. The residual material was separated by silica gelcolumn chromatography (10:90 ethyl acetate:hexane) to afford4-bis(tert-butoxycarbonyl)amino-6-(3,5-dimethylisoxazol-4-yl)-2-(methylthio)pyrimidineas an off-white solid (920 mg, 2.11 mmol, 50%); m.p. 88-89° C.; TLCR_(F) 0.12 (10:90 ethyl acetate:hexane). ¹H NMR (500 MHz, CDCl₃) δ 7.50(1H, s), 2.66 (3H, s), 2.52 (3H, s), 2.49 (3H, s), 1.56 (18H, s).

Step 3. A solution of4-bis(tert-butoxycarbonyl)amino-6-(3,5-dimethylisoxazol-4-yl)-2-(methylthio)pyrimidine(920 mg, 2.11 mmol) in dichloromethane (50 mL) was treated withm-chloroperbenzoic acid (1.86 g, ca. 70% w/w, 7.54 mmol) in smallportions over 20 minutes. The mixture was allowed to stir at ambienttemperature for 12 hours, was diluted with dichloromethane (150 mL),then washed twice with an aqueous Na₂CO₃ solution (150 mL, 2N), water(150 mL) and saturated brine (100 mL), dried over Na₂SO₄, then filteredand the remaining liquid evaporated. The crude4-bis(tert-butoxycarbonyl)amino-6-(3,5-dimethylisoxazol-4-yl)-2-(methylsulfonyl)pyrimidinewas used in the next step without further purification: m.p. 111-113° C.¹H NMR (500 MHz, CDCl₃) δ 8.13 (1H, s), 3.28 (3H, s), 2.75 (3H, s), 2.55(3H, s), 1.59 (18H, s).

Step 4. A mixture of4-bis(tert-butoxycarbonyl)amino-6-(3,5-dimethylisoxazol-4-yl)-2-(methylsulfonyl)pyrimidine(235 mg, 0.502 mmol) and N-(4-chlorophenyl)formamide (158 mg, 1.02 mmol)in dioxane (5 mL) was treated with sodium hydride (80 mg, 3.33 mmol,previously washed free of mineral oil). The mixture was stirred atambient temperature for 12 hours, was treated with methanol (1 mL) thenstirred for one additional hour. The mixture was poured into water (30mL) and extracted twice with ethyl acetate (30 mL). The extracts werewashed with water and brine (30 mL each) and combined, then dried overNa₂SO₄, filtered and liquids evaporated. To the crude material was addeddichloromethane (10 mL) and the mixture was treated with trifluoroaceticacid (2 mL). The mixture was stirred for 4 hours, liquids wereevaporated and a saturated aqueous NaHCO₃ solution (20 mL) was added.The mixture was extracted with dichloromethane (30 mL). The extract wasdried over Na₂SO₄, then filtered and the remaining liquid evaporated.The crude product was purified by triuration in ether, collected byfiltration and dried under vacuum to afford the title compound as apowder (42 mg, 0.133 mmol, 26%); m.p. 120-122° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.42 (1H, br s), 7.82 (2H, d, J=8.9 Hz), 7.31 (2H, d, J=8.9Hz), 7.02 (2H, br s), 6.15 (1H, s), 2.40 (3H, s), 2.32 (3H, s). MS (ES+)m/e 318.2 (35), 316.2 (100).

Additional compounds of Formula (I) or a form thereof described hereinmay be prepared according to the procedure of Example 24 by substitutingthe appropriate starting materials, reagents and reaction conditions:

Cpd Name and Data 3 N²-[4-(trifluoromethyl)phenyl]-6-(1, 3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine-2, 4- diamine MS m/z 363 [M + H]⁺189 6-(3, 5-dimethyl-1, 2-oxazol-4-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (1H, v br), 7.62 (2H, d, J =8.6 Hz), 6.93 (2H, br s), 6.89 (2H, d, J = 8.6 Hz), 6.09 (1H, s), 3.75(3H, s), 2.60 (3H, s), 2.39 (3H, s); m.p.: 89-91° C.; MS m/z 312.2 [M +H]⁺ 190 6-(3, 5-dimethyl-1,2-oxazol-4-yl)-N²-(4-methylphenyl)pyrimidine-2, 4-diamine ¹H NMR (500MHz, DMSO-d₆) δ 8.88 (1H, br s), 7.65 (2H, d, J = 8.4 Hz), 7.08 (2H, d,J = 8.4 Hz), 6.71 (2H, br s), 6.09 (1H, s), 2.61 (3H, s), 2.40 (3H, s),2.27 (3H, s); MS m/z 297.3 [M + H]⁺

Example 253-{[4-(imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino}benzamide (Cpd75)

To 3-((4-(imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid(40 mg, 0.12 mmol), ACN (1 mL), CDI (excess) and DMF (1 mL) were addedat room temperature. The mixture was stirred at room temperature for 20minutes, heated to 60° C. for 1 hour and 20 minutes, then cooled to roomtemperature. Ammonium hydroxide (conc. aqueous, 1 mL) was added. Thereaction mixture was allowed to stand for 15 minutes at roomtemperature, then the solid material was collected by filtration, washedwith water and dried to provide the title compound as a white solid (28mg, 70%). ¹H NMR (DMSO-d₆) δ 10.10 (br. s, 1H), 9.82 (s, 1H), 8.64 (s,1H), 8.45-8.48 (m, 1H), 8.19-8.25 (m, 1H), 7.94 (br. s, 1H), 7.90 (br.d, J=8.8 Hz, 1H), 7.77 (d, J=9.1 Hz, 1H), 7.47-7.53 (m, 2H), 7.43-7.46(m, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.36 (br. s, 1H), 7.10 (t, J=6.6 Hz,1H).

Example 266-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine(Cpd 128)

Step 1. A mixture of1-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole(317 mg, 0.982 mmol) and N-p-tolylformamide (146 mg, 1.08 mmol) in 5 mLdioxane was cooled to 0° C. and treated with sodium hydride (previouslywashed free of mineral oil, 26 mg, 1.08 mmol). The mixture was allowedto warm to ambient temperature, was stirred overnight, then was pouredinto four volumes of water. The mixture was extracted with ethyl acetate(2×20 mL), and the extracts were washed with saturated brine thencombined and dried over Na₂SO₄. The product was filtered and evaporatedto affordN-(4-chloro-6-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)-N-p-tolylformamide,which was used in the next step without further purification. MS (ES+):m/e 380 (35), 378 (100).

Step 2.N-(4-chloro-6-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)-N-p-tolylformamidewas dissolved in DMSO (5 mL) and delivered to a thick-walled tube, towhich ammonium hydroxide (conc.) (1 mL) was added. The tube was sealedand heated to 90° C. for 48 hours, then cooled and the contents pouredinto four volumes of water. The resulting precipitate was collected byfiltration, dried under vacuum and triturated with a small amount ofdichloromethane. The purified product was collected by filtration anddried under vacuum to provide the title compound (236 mg, 0.714 mmol,73% for 2 steps): m.p. 174-175° C. ¹H NMR (500 MHz, DMSO-d₆): δ 9.18(1H, s), 7.68 (2H, d, J=8.4 Hz), 7.67-7.61 (2H, m), 7.30-7.26 (2H, m),7.07 (2H, d, J=8.4 Hz), 7.01 (2H, br), 6.13 (1H, s), 2.70 (3H, s), 2.27(3H, s). MS (ES+): m/e 332.2 (20), 331.2 (100). MS (ES−): m/e 330.1(20), 329.1 (100).

BIOLOGICAL EXAMPLES

The following biological examples demonstrate the usefulness of thecompounds of Formula (I) or a form thereof described herein to inhibitBmi-1 function and reduce the level of Bmi-1.

Example 1

Sandwich ELISA Assay

Cell Seeding and Compound Treatment (Day 1):

HT-1080 cells were seeded at 8000 cells/well (50 μL) in 96-well tissueculture plates. After the cells became adherent (3-4 hours), 2× dilutedstocks of test compounds in 50 μL DMEM containing 1% DMSO (final DMSOconcentration was 0.5%) were added and the plates were incubated at 37°C. under 5% CO₂ for 40-48 hours.

ELISA Plate First Antibody Preparation (Day 2):

The First Antibody (Millipore Mouse, monoclonal to mouse Bmi-1, cloneF6, catalog #05-637) diluted to 2 μg/mL in PBS was added (100 μL) toeach well of a Nunc MaxiSorp 96-well ELISA plate. The plate was coveredwith a plate seal and allowed to stand overnight.

Cell Lysate Preparation (Day 3):

Fresh Lysis buffer (1×) was prepared on the day of the assay as follows:1 mM EDTA, 150 mM NaCl, 0.5% Triton-X 100, 10 mM NaF, 20 mMB-Glycerophosphate, 1 mM DTT (in PBS, pH 7.2-7.4) and HALT proteaseinhibitor cocktail (1×) (Pierce #78410).

Lysis Buffer (1×, 40 μL) was added to each well and the plate was shakenfor 5-10 minutes on an orbital shaker to allow cell lysis, then diluent(1% BSA in PBS in 0.5% NP40) (100 μL) was added to each well.

A standard curve was prepared at the following Bmi-1 concentrations:8000, 4000, 2000, 1000, 500, 250, 125 and 0 pg/mL. The Bmi-1 RecombinantProtein Standard (Novus Biologicals PCGF4 Recombinant Protein (P01),catalog # H00000648-P01) used to prepare the standard curve was storedat −80° C. On first thaw, the Recombinant Protein Standard was dilutedto 10 μg/μL in Blocking Buffer (1% BSA in PBS; BSA: Fisher ScientificCatalog #1600-100). Aliquots were taken and refrozen at −80° C. Thealiquots may be kept at 4° C. and reused after first thaw, but onlywithin 1-2 weeks. The Recombinant Protein Standard contains a GST-fusiontag that appears at approximately 70 Kda on Western Blot.

ELISA Assay (Day 3):

The prepared ELISA plate was washed 3× with Wash Buffer (0.05% Tween-20in PBS). The final wash was removed from the plate and the plate wasblotted dry. Blocking Buffer (300 μL) (1% BSA in PBS) was added to eachwell. The plate was covered with a plate seal and incubated at roomtemperature for 1 hour. The blocked plate was washed 3× with WashBuffer, then the final wash was removed and the plate was blotted dry.The previously prepared samples and standards were added (100 μL/well)and the plate was covered with a plate seal and incubated at 4° C.overnight.

ELISA Assay (Day 4):

The prepared ELISA plate was removed from incubation and allowed tostand at room temperature for 30 minutes, then washed and blotted dry.The Second Antibody (Cell Signaling Rabbit anti-Bmi-1, Cat#2830) dilutedto 1:600 in Blocking Buffer was added (100 μL) to each well, except asneeded for background control wells. The plate was covered with a plateseal and incubated for 1.5 hrs at room temperature.

The ELISA plate was washed and blotted dry as previously described. TheThird Antibody (Cell Signaling HRP conjugated anti-rabbit IgG(CellSignaling, Cat#:7074) diluted to 1:300 in Blocking Buffer was added(100 μL) to each well, except as needed for background control wells.The plate was incubated for 1 hr at room temperature.

The plate was washed and blotted dry, then a previously prepared TMBsubstrate (TMB substrate kit, Pierce catalog #34021) (prepared by mixingkit reagents 1:1) (100 μL) was added per well. The plate was incubatedfor 20-30 minutes at room temperature in the dark, then Stop Solution (2M sulfuric acid in water) (50 μL) was added per well. The plates wereread at OD450 (experimental) and OD570 (reference).

As shown in Table 1, an ELISA EC₅₀ value for Bmi-1 protein provided bytest compounds of Formula (I) or a form thereof described hereinbetween >0.1 μM and ≤3.0 μM is indicated by one star (*), an EC₅₀ valuebetween >0.01 μM to ≤0.1 μM is indicated by two stars (**), an EC₅₀value between >0.001 μM to ≤0.01 μM is indicated by three stars (***)and an EC₅₀ value of ≤0.001 μM is indicated by four stars (****).

TABLE 1 Cpd EC₅₀ 1 *** 2 *** 3 *** 4 ** 5 ** 6 * 7 ** 8 * 9 *** 10 ** 11** 12 ** 13 * 14 ** 15 * 16 * 17 * 18 * 19 * 20 ** 21 * 22 ** 23 ** 24 *25 * 26 ** 27 ** 28 *** 29 ** 30 * 31 *** 32 ** 33 ** 34 ** 35 ** 36 *37 ** 38 * 39 ** 40 ** 41 ** 42 ** 43 ** 44 ** 45 ** 46 * 47 * 48 **49 * 50 ** 51 ** 52 * 53 ** 54 *** 55 ** 56 * 57 ** 58 * 59 * 60 ** 61** 62 * 63 * 64 ** 65 ** 66 *** 67 * 68 * 69 ** 70 ** 71 ** 72 ** 73 *74 * 75 * 76 ** 77 ** 78 ** 79 ** 80 ** 81 * 82 ** 83 ** 84 ** 85 **86 * 87 ** 88 *** 89 ** 90 ** 91 ** 92 ** 93 ** 94 ** 95 ** 96 * 97 **98 ** 99 ** 100 *** 101 *** 102 ** 103 ** 104 ** 105 ** 106 * 107 *108 * 109 ** 110 * 111 ** 112 * 113 ** 114 ** 115 * 116 * 117 * 118 *119 * 120 ** 121 ** 122 ** 123 ** 124 ** 125 ** 126 * 127 * 128 *** 129**** 130 *** 131 ** 132 * 133 *** 134 *** 135 ** 136 *** 137 * 138 *139 * 140 * 141 * 142 *** 143 * 144 *** 145 * 146 * 147 * 148 *** 149*** 150 *** 151 *** 152 * 153 *** 154 ** 155 *** 156 ** 157 ** 158 ***159 * 160 *** 161 *** 162 ** 163 * 164 * 165 * 166 * 167 * 168 *** 169 *170 *** 171 *** 172 *** 173 * 174 ** 175 ** 176 ** 177 ** 178 *** 179 **180 *** 181 *** 182 ** 183 ** 184 * 185 ** 186 ** 187 ** 188 ** 189 *190 * 191 * 192 * 193 * 194 * 195 * 196 * 197 * 198 * 199 *

The following publications are incorporated by reference into thepresent application for any and all purposes to the same extent as ifeach individual publication was fully set forth herein:

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Without regard to whether a document cited herein was specifically andindividually indicated as being incorporated by reference, all documentsreferred to herein are incorporated by reference into the presentapplication for any and all purposes to the same extent as if eachindividual reference was fully set forth herein.

Although certain embodiments have been described in detail above, thosehaving ordinary skill in the art will clearly understand that manymodifications are possible in the embodiments without departing from theteachings thereof. All such modifications are intended to be encompassedwithin the scope of the claims presented herein.

What is claimed is:
 1. A compound of Formula (I):

or a form thereof, wherein X is N or N substituted with an oxygen atomsubstituent to form an N-oxide; R₁ is bicyclic heteroaryl selected fromthe group consisting of 1H-indolyl, 2H-indazolyl, 1H-benzimidazolyl,pyrazolo[1,5-a ]pyridinyl, pyrazolo[1,5-c]pyrimidinyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c ]pyridinyl, imidazo[1,2-a]pyrazinyl,7H-purinyl and quinolinyl, wherein the heteroatom is N, wherein thebicyclic heteroaryl is substituted on a carbon atom ring member withone, two, three or four R₅ substituents or on a nitrogen atom ringmember with an oxygen atom substituent to form an N-oxide; R₂ is cyano,hydroxyl, nitro, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,hydroxyl-amino, hydroxyl-C₁₋₈alkyl-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,C₁₋₈alkyl-thio, C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-amino,amino-carbonyl, C₁₋₈alkyl-amino-carbonyl, (C₁₋₈alkyl)₂-amino-carbonyl,amino-carbonyl-amino, C₁₋₈alkyl-amino-carbonyl-amino,(C₁₋₈alkyl)₂-amino-carbonyl-amino, C₁₋₈alkoxy-carbonyl,C₁₋₈alkoxy-carbonyl-amino, amino-sulfonyl, C₁₋₈alkyl-amino-sulfonyl,(C₁₋₈alkyl)₂-amino-sulfonyl, amino-sulfonyl-amino,C₁₋₈alkyl-amino-sulfonyl-amino, (C₁₋₈alkyl)₂-amino-sulfonyl-amino,P(O)(R₇)₂-amino or heteroaryl, wherein heteroaryl is optionallysubstituted with one, two, three or four C₁₋₈alkyl substituents; R₃ishydrogen, cyano, halo, C₁₋₈alkyl, amino, C₁₋₈alkyl-amino or(C₁₋₈alkyl)₂-amino; R₄ is C₃₋₁₄cycloalkyl, aryl, heteroaryl orheterocyclyl, each optionally substituted with one, two, three or fourR₆ substituents; R₅ is independently selected from the group consistingof cyano, halo, hydroxyl, nitro, oxo, C₁₋₈alkyl, cyano-C₁₋₈alkyl,halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,halo-C₁₋₈alkoxy, C₂₋₈alkenyl, C₁₋₈alkoxy-C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy-C₂₋₈alkynyl, carboxyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl-amino,hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-thio,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkyl-carbonyl-oxy,C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,C₁₋₈alkoxy-carbonyl-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl-amino,C₁₋₈alkyl-sulfonyl, C₃₋₁₄cycloalkyl, aryl, aryl-C₁₋₈alkyl, aryl-amino,aryl-C₁₋₈alky-amino, heteroaryl, heteroaryl-C₁₋₈alkyl and heterocyclyl,wherein C₃₋₁₄cycloalkyl, aryl, heteroaryl or heterocyclyl and the aryland heteroaryl portions of aryl-C₁₋₈alkyl, aryl-amino,aryl-C₁₋₈alky-amino and heteroaryl-C₁₋₈alkyl are each optionallysubstituted with one, two, three or four halo, C₁₋₈alkyl,halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,hydroxyl-C₁₋₈alkoxy or carboxyl substituents; R₆ is independentlyselected from the group consisting of cyano, halo, hydroxyl, nitro,C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₂₋₈alkenyl, C₁₋₈alkoxy-C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy-C₂₋₈alkynyl, carboxyl, formyl, formyl-oxy,C₁₋₈alkyl-carbonyl, halo-C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-thio,halo-C₁₋₈alkyl-thio, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,C₁₋₈alkyl-carbonyl, C₁₋₈alkyl-carbonyl-oxy,C₁₋₈alkyl-carbonyl-oxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,halo-C₁₋₈alkoxy-carbonyl, C₁₋₈alkoxy-carbonyl-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino-C₁₋₈alkyl,amino-carbonyl, C₁₋₈alkyl-amino-carbonyl, (C₁₋₈alkyl)₂-amino-carbonyl,C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkyl-carbonyl-amino-C₁₋₈alkyl,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,hydroxyl-C₁₋₈alkyl-amino, hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, imino-C₁₋₈alkyl,hydroxyl-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyl, halo-C₁₋₈alkyl-sulfonyl, amino-sulfonyl,C₁₋₈alkyl-amino-sulfonyl, (C₁₋₈alkyl)₂-amino-sulfonyl, B(OR₈)₂,C₃₋₁₄cycloalkyl, heterocyclyl, aryl and heteroaryl, whereinC₃₋₁₄cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionallysubstituted with one, two, three or four halo or C₁₋₈alkyl substituents;R₇ is independently hydroxyl or (C₁₋₈alkoxy)_(n), wherein n representsan integer from 1 to 5; and, R₈ is independently hydrogen or C₁₋₈alkyl;wherein the form of the compound is selected from the group consistingof a salt, hydrate, solvate, stereoisomer, racemate, enantiomer,diastereomer and tautomer thereof.
 2. The compound of claim 1, whereinR₁ is substituted bicyclic heteroaryl selected from the group consistingof 1H-benzimidazolyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-c]pyrimidinyl, 1H-imidazo[4,5-b]pyridinyl, and quinolinyl.3. A compound or a form thereof selected from the group consisting of:N²-[4-(trifluoromethyl)phenyl]-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine4-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine4-chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amineN²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-2,4-diamineN²-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine2-{[6-(2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol2-{[2-{[3-fluoro-4-(trifluoromethyl)phenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol2-{[2-{[4-(difluoromethoxy)-3-fluorophenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol4-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine4-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-2-amine6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine2-{[6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanolN⁴-hydroxy-6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-ethyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(quinolin-4-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine4-chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amine6-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(6-chloro-2-ethyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine4-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine6-(2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine4-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine6-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine-6-(2,6-dimethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine6-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-ol6-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(5,7-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2,6-dimethyl-1H-benzimidazol-1-yl)-N²-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(2,6-dimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine5-fluoro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine5-fluoro-6-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine6-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-[2-(propan-2-yl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(methoxymethyl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine6-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-[5-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine6-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-[2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine6-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4-diamine6-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine6-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-ethyl-1H-benzimidazol-1-yl)-N²-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine6-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(trifluoromethyl)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidine-2,4-diamine[6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]phosphoramidicacid6-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)pyrimidine-2,4-diamine6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)-3 -fluorophenyl]-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)p yrimidine-2,4-diamine6-(2-cyclopropyl-5-methoxypyrazolo [1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-4-oxido-1H-imidazo[4,5-b]pyridin-1-yl-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(5-fluoro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide6-(2-ethyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide4-chloro-6-(5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine6-(5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine3-oxide6-(2-cyclopropyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide3-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-2,5,6-trimethylpyrazolo[1,5-c]pyrimidin-7(6H)-one6-(2-ethyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide6-(5-amino-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(5-chloro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine6-(5-chloro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(5-chloro-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(5-chloro-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine6-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine6-(2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine6-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamineN²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-bromophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(dimethylamino)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine4-{[4-amino-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-fluorophenyl)pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamineN²-(3-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(3-fluoro-4-methoxyphenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-phenylpyrimidine-2,4-diamineN²-[4-(dimethylamino)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine4-{[4-amino-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethoxy)phenyl[pyrimidine-2,4-diamineN²-(2,2-difluoro-1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(3-fluoro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(3-chloro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-ethyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine6-(2-ethyl-1H-benzimidazol-1-yl)-N²-(2-methylphenyl)pyrimidine-2,4-diamine6-(2-ethyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamineN²-(1,3-benzodioxol-5-yl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-ethyl-1H-benzimidazol-1-yl)-N²-(3-fluoro-4-methoxyphenyl)pyrimidine-2,4-diamineN²-(3-chloro-4-methoxyphenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(6-methoxypyridin-3-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-phenylpyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamineN²-[4-(dimethylamino)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-fluorophenyl)pyrimidine-2,4-diamineN²-(3-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamine6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine4-{[4-amino-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N²-(3-fluoro-4-methoxyphenyl)pyrimidine-2,4-diamineN²-(4-chloro-3-fluorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-chloro-3-fluorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine5-fluoro-N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamineN²-(4-chloro-3-fluorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-methylphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(3-fluoro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(3-chloro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-[4-(difluoromethoxy)phenyl]-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(3,5-dimethyl-1,2-oxazol-4-yl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine6-(3,5-dimethyl-1,2-oxazol-4-yl)-N²-(4-methylphenyl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-chloro-3-fluorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(3-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methylphenyl)pyrimidine-2,4-diamine6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamine5-chloro-N²-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamineN²-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)pyrimidine-2,4-diamine;and,6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide;wherein the form of the compound is selected from the group consistingof a salt, hydrate, solvate, stereoisomer, racemate, enantiomer,diastereomer and tautomer thereof.
 4. The compound of claim 3 selectedfrom the group consisting of:6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diaminemethanesulfonate6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diaminehydrochloride6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diaminemethanesulfonate6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diaminehydrochloride6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diaminehydrobromide6-(2-methyl-1H-benzimidazol-1-yl)-N²-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diaminesulfate (2:1); and, disodium[6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]phosphoramidate;wherein the form of the compound is selected from the group consistingof a free acid, free base, hydrate, solvate, stereoisomer, racemate,enantiomer, diastereomer and tautomer thereof.
 5. A pharmaceuticalcomposition comprising an effective amount of the compound of claim 1 inadmixture with a pharmaceutically acceptable excipient.
 6. Apharmaceutical composition comprising an effective amount of thecompound of claim 3 in admixture with a pharmaceutically acceptableexcipient.
 7. The compound of claim 1, wherein R₂ is cyano, hydroxyl,amino, hydroxyl-amino, or P(O)(R₇)₂-amino.